K-Ras(G12C) inhibitor 12 is an allosteric inhibitor of oncogenic K-Ras(G12C).

K-Ras G12C-IN-4, is a potent Covalent Inhibitor of KRASG12C..

K-Ras(G12C) inhibitor 9 is an allosteric inhibitor of oncogenic K-Ras(G12C).

PI3K/mTOR Inhibitor-12, a potent and selective orally active inhibitor, exhibits IC50 values of 0.06 nM for PI3Kα and 3.12 nM for mTOR, indicating significant antitumor activity with reduced liver toxicity [1].

PI3Kδ-IN-12 (compound 13), a PI3Kδ inhibitor with a pIC50 of 5.8, exhibits differential binding affinities with pKi values of 8.0 for PI3Kδ, 6.5 for PI3Kγ, 6.4 for PI3Kβ, and 6.7 for PI3Kα. This compound is utilized in researching chronic respiratory conditions, including asthma and chronic obstructive pulmonary disease (COPD) [1].

PI3Kα-IN-12 (compound 13), a potent and selective PI3Kα inhibitor (IC50: 1.2 nM), effectively suppresses HCT-116 and U87-MG cell proliferation with IC50 values of 0.83 and 1.25 μM, respectively. Intraperitoneal administration of PI3Kα-IN-12 (40 mg/kg) induces tumor regression in a mouse xenograft model bearing U87-MG cells [1].

K-Ras(G12C) inhibitor 6 is an irreversible, allosteric inhibitor of the K-Ras(G12C) mutant that causes 100% modification of the protein when used at 10 μM for 24 hours in vitro.

Senicapoc (ICA-17043) is a potent inhibitor of the Gardos channel and ameliorates RBC dehydration in the SAD mouse. Senicapoc blocked Ca2+-induced rubidium flux from human RBCs with an IC50 value of 11 ± 2 nM (CLT IC50 = 100 ± 12 nM) and inhibited RBC dehydration with an IC50 of 30 ± 20 nM. Senicapoc is in treatment of Sickle Cell Disease and Sickle Cell Anemia

Alphitonin is a flavonoid that has been found in L. leptolepis wood.1 It is also a metabolic intermediate that is formed during the catabolism of quercetin by the human gut bacteria E. ramulus.2,3 |1. Chen, K., Ohmura, W., Doi, S., et al. Termite feeding deterrent from Japanese larch wood. Bioresour. Technol. 95(2), 129-134 (2004).|2. Braune, A., Gütschow, M., Engst, W., et al. Degradation of quercetin and luteolin by Eubacterium ramulus. Appl. Environ. Microbiol. 67(12), 5558-55567 (2001).|3. Jaganath, I.B., Mullen, W., Lean, M.E.J., et al. In vitro catabolism of rutin by human fecal bacteria and the antioxidant capacity of its catabolites. Free Radic. Biol. Med. 47(8), 1180-1189 (2009).

C26 Sphingomyelin is a sphingolipid that has been found in serum and cell or brain extracts.1,2,3C26 sphingomyelin levels are increased in the serum of patients with hemophagocytic lymphohistiocytosis, an inflammatory condition characterized by excessive immune activation.3C26 sphingomyelin has been used a component of monolayers to study the influence of sphingomyelin acyl chain length on sphingomyelin-sterol interactions.4[Matreya, LLC.] 1.Wang, J.-R., Zhang, H., Yau, L.D., et al.Improved sphingolipidomic approach based on ultra-high performance liquid chromatography and multiple mass spectrometries with application to cellular neurotoxicityAnal. Chem.86(12)5688-5696(2014) 2.Willmann, J., Mahlstedt, K., Leibfritz, D., et al.Characterization of sphingomyelins in lipid extracts using a HPLC-MS-offline-NMR methodAnal. Chem.79(11)4188-4191(2007) 3.Jenkins, R.W., Clarke, C.J., Lucas, J.T., Jr., et al.Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosisAm. J. Hematol.88(11)E265-E272(2013) 4.Li, X.M., Momsen, M.M., Brockman, H.L., et al.Sterol structure and sphingomyelin acyl chain length modulate lateral packing elasticity and detergent solubility in model membranesBiophys. J.85(6)3788-3801(2003)

Napyradiomycin A1is a fungal metabolite originally isolated fromC. rubraand has diverse biological activities.1,2It is active againstS. aureus,M. luteus,B. anthracis,C. bovis, andM. smegmatis(MICs = 1.56-12.5 μg/ml).1Napyradiomycin A1is an estrogen receptor antagonist (IC50= 4.2 μM in rat uterine homogenates).2It also inhibits mitochondrial NADH:ubiquinone oxidoreductase (complex I) and succinate:ubiquinone oxidoreductase (complex II) activities in bovine heart homogenates (IC50s = 20 and 9.7 μM, respectively).3 1.Shiomi, K., Iinuma, H., Hamada, M., et al.Novel antibiotics napyradiomycins. Production, isolation, physico-chemical properties and biological activityJ. Antibiot. (Tokyo)39(4)487-493(1986) 2.Hori, Y., Abe, Y., Shigematsu, N., et al.Napyradiomycins A and B1: Non-steroidal estrogen-receptor antagonists produced by a StreptomycesJ. Antibiot. (Tokyo)46(12)1890-1893(1993) 3.Yamamoto, K., Tashiro, E., Motohashi, K., et al.Napyradiomycin A1, an inhibitor of mitochondrial complexes I and IIJ. Antibiot. (Tokyo)65(4)211-214(2012)

Betamethasone 21-phosphate is a synthetic glucocorticoid.1It prevents increases in macrophage and eosinophil numbers in bronchoalveolar lavage fluid (BALF) and decreases in blood leukocyte numbers in a guinea pig model of parainfluenza-3 viral infection when administered at a dose of 8 mg/kg but does not prevent airway hyperresponsiveness after infection.2Betamethasone 21-phosphate inhibits cell infiltration into the aqueous humor in a rat model of endotoxin-induced uveitis when administered topically or subcutaneously at doses of 0.01-1% or 1 mg/kg, respectively.3It increases maximal lung pressure volume curves in fetal sheep when administered to pregnant ewes at 0.75 gestation at doses of 80 and 170 μg/kg.1Betamethasone 21-phosphate increases body weight, impairs learning and memory, increases anxiolytic behavior, and reduces hippocampal neurogenesis in CD-1 mice but reduces body weight and increases neurogenesis with no effect on anxiety in high-anxiety DBA/2 mice when administered at a dose of approximately 25 mg/kg per day in the drinking water for seven weeks.4Formulations containing betamethasone 12-phosphate and betamethasone acetate have been used in the treatment of severe allergic conditions and a variety of immune-related conditions. 1.Loehle, M., Schwab, M., Kadner, S., et al.Dose-response effects of betamethasone on maturation of the fetal sheep lungAm. J. Obstet. Gynecol.202(2)186.e181-186.e187(2010) 2.Leusink-Muis, A., Ten Broeke, R., Folkerts, G., et al.Betamethasone prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigsClin. Exp. Allergy29(Suppl. 2)82-85(1999) 3.Tsuji, F., Sawa, K., Kato, M., et al.The effects of betamethasone derivatives on endotoxin-induced uveitis in ratExp. Eye Res.64(1)31-36(1997) 4.Aiello, R., Crupi, R., Leo, A., et al.Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesisBehav. Brain Res.278155-166(2015)

9(S),12(S),13(S)-TriHOME is a linoleic acid-derived oxylipin that has diverse biological activities.1,2,3,4It has been found in various plants and is produced in human eosinophils in a 15-lipoxygenase-dependent, soluble epoxide hydrolase-independent manner.1,59(S),12(S)13(S)-TriHOME inhibits antigen-induced β-hexosaminidase release from RBL-2H3 mast cells (IC50= 28.7 μg/ml).2It inhibits LPS-induced nitric oxide (NO) production in BV-2 microglia (IC50= 40.95 μM).3In vivo, 9(S),12(S),13(S)-TriHOME (1 g/animal) enhances the antiviral IgA and IgG antibody responses induced by a nasal influenza hemagglutinin (HA) vaccine by 5.2- and 2-fold, respectively, in mice.4 1.Hamberg, M., and Hamberg, G.Peroxygenase-catalyzed fatty acid epoxidation in cereal seeds: Sequential oxidation of linoleic acid into 9(S),12(S),13(S)-trihydroxy-10(E)-octadecenoic acidPlant Physiol.110(3)807-815(1996) 2.Hong, S.S., and Oh, J.S.Inhibitors of antigen-induced degranulation of RBL-2H3 cells isolated from wheat branJ. Korean Soc. Appl. Biol. Chem.5569-74(2012) 3.Kim, C.S., Kwon, O.W., Kim, S.Y., et al.Five new oxylipins from Chaenomeles sinensisLipids49(11)1151-1159(2014) 4.Shirahata, T., Sunazuka, T., Yoshida, K., et al.Total synthesis, elucidation of absolute stereochemistry, and adjuvant activity of trihydroxy fatty acidsTetrahedron62(40)9483-9496(2006) 5.Fuchs, D., Tang, X., Johnsson, A.-K., et al.Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent processBiochim. Biophys. Acta Mol. Cell Biol. Lipids1865(4)158611(2020)

trans-carboxy Glimepiride is a metabolite of the sulfonylurea glimepiride .1It is formed from glimepiride in a two-step process mediated by the cytochrome P450 (CYP) isoform CYP2C9 and cytosolic enzymes. 1.Noh, K., Kim, E., Jeong, T.C., et al.Simultaneous determination of glimepiride and its metabolites in human plasma by liquid chromatography coupled to a tandem mass spectrometryArch. Pharm. Res.34(12)2073-2078(2011)

17R(18S)-EpETE is an oxylipin and a cytochrome P450 metabolite of eicosapentaenoic acid .1,217R(18S)-EpETE is an activator of large-conductance calcium-activated potassium (BKCa) channels, increasing the potassium current amplitude by 15-fold in isolated rat cerebral artery vascular smooth muscle cells (VSMCs) at +60 mV when used at a concentration of 50 nM.2It has negative chronotropic effects in isolated neonatal rat cardiomyocytes (NRCMs; EC50= ~1-2 nM) and prevents calcium-induced increases in the spontaneous beating of NRCMs.3,4 1.Schwarz, D., Kisselev, P., Ericksen, S.S., et al.Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: Highly steroselective formation of 17(R), 18(S)-epoxyeicosatetraenoic acidBiochem. Pharmacol.67(8)1445-1457(2004) 2.Lauterbach, B., Barbosa-Sicard, E., Wang, M.H., et al.Cytochrome P450-dependent eicosapentaenoic acid metabolites are novel BK channel activatorsHypertension39(2 Pt. 2)609-613(2002) 3.Falck, J.R., Wallukat, G., Puli, N., et al.17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analoguesJ. Med. Chem.54(12)4109-4118(2011) 4.Arnold, C., Markovic, M., Blossey, K., et al.Arachidonic acid-metabolizing cytochrome P450 enzymes are targets of omega-3 fatty acidsJ. Biol. Chem.285(43)32720-32733(2010)

5'-pApA is a linearized form of cyclic di-AMP, a bacterial second messenger that activates the host innate immune system through stimulator of interferon genes (STING).1,2,3,4It is a metabolite of cyclic di-AMP formedviahydrolysis by various phosphodiesterases (PDEs).55'-pApA is intended for use as a negative control for cyclic di-AMP signaling. 1.Burdette, D.L., Monroe, K.M., Sotelo-Troha, K., et al.STING is a direct innate immune sensor of cyclic-di-GMPNature478(7370)515-518(2011) 2.Parvatiyar, K., Zhang, Z., Teles, R.M., et al.DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune responseNat. Immunol.13(12)1155-1161(2012) 3.Woodward, J.J., Iavarone, A.T., and Portnoy, D.A.c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon responseScience328(5986)1703-1705(2010) 4.Witte, C.E., Whiteley, A.T., Burke, T.P., et al.Cyclic di-AMP is critical for Listeria monocytogenes growth, cell wall homeostasis, and establishment of infectionmBio4(3)e00282-00213(2013) 5.Fahmi, T., Port, G.C., and Cho, K.H.c-di-AMP: An essential molecule in the signaling pathways that regulate the viability and virulence of gram-positive bacteriaGenes (Basel)8(8)197(2017)

Aquastatin A is a fungal metabolite originally isolated fromF. aquaeductuumthat has diverse biological activities.1It is active againstS. aureus(MIC = 32 μg/ml) and inhibits enoyl-acyl carrier protein reductase (Fabl; IC50= 3.2 μM) andS. aureusfatty acid synthesis (IC50= 3.5 μM).2Aquastatin A also inhibits the Na+/K+-ATPase and H+/K+-ATPase (IC50s = 7.1 and 6.2 μM, respectively), as well as protein tyrosine phosphatase 1B (PTP1B; IC50= 0.19 μM).1,3 1.Hamano, K., Kinoshita-Okami, M., Minagawa, K., et al.Aquastatin A, an inhibitor of mammalian adenosine triphosphatases from Fusarium aquaeductuum. Taxonomy, fermentation, isolation, structure determination and biological propertiesJ. Antibiot. (Tokyo)46(11)1648-1657(1993) 2.Kwon, Y.-J., Fang, Y., Xu, G.-H., et al.Aquastatin A, a new inhibitor of enoyl-acyl carrier protein reductase from Sporothrix sp. FN611Biol. Pharm. Bull.32(12)2061-2064(2009) 3.Seo, C., Soh, J.H., Oh, H., et al.Isolation of the protein tyrosine phosphatase 1B inhibitory metabolite from the marine-derived fungus Cosmospora sp. SF-5060Bioorg. Med. Chem. Lett.19(21)6095-6097(2009)

BE-24566B is a polyketide fungal metabolite originally isolated fromS. violaceusniger.1It is active againstB. subtilis,B. cereus,S. aureus,M. luteus,E. faecalis, andS. thermophilus(MICs = 1.56, 1.56, 1.56, 1.56, 3.13, and 3.13 μg/ml, respectively). BE-24566B is an endothelin (ET) receptor antagonist (IC50s = 11 and 3.9 μM for ETAand ETBreceptors, respectively).2 1.Kojiri, K., Nakajima, S., Fuse, A., et al.BE-24566B, a new antibiotic produced by Streptomyces violaceusnigerJ. Antibiot. (Tokyo)48(12)1506-1508(1995) 2.Lam, Y.K.T., Hensens, O., Helms, G., et al.L-755,805, a new polyketide endothelin binding inhibitor from an actinomyceteTetrahedron Lett.36(12)2013-2016(1995)

Palmitic acid-13C is intended for use as an internal standard for the quantification of palmitic acid by GC- or LC-MS. Palmitic acid is a 16-carbon saturated fatty acid. It comprises approximately 25% of human total plasma lipids.1 It increases protein levels of COX-2 in RAW 264.7 cells when used at a concentration of 75 μM.2 Palmitic acid is involved in the acylation of proteins to anchor membrane-bound proteins to the lipid bilayer.2,3,4,5,6 |1. Santos, M.J., López-Jurado, M., Llopis, J., et al. Influence of dietary supplementation with fish oil on plasma fatty acid composition in coronary heart disease patients. Ann. Nutr. Metab. 39(1), 52-62 (1995).|2. Lee, J.Y., Sohn, K.H., Rhee, S.H., et al. Saturated fatty acids, but not unsaturated fatty acids, induced the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J. Biol. Chem. 276(20), 16683-16689 (2001).|3. Dietzen, D.J., Hastings, W.R., and Lublin, D.M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270(12), 6838-6842 (1995).|4. Robinson, L.J., and Michel, T. Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc. Nat. Acad. Sci. USA 92(25), 11776-11780 (1995).|5. Topinka, J.R., and Bredt, D.S. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 20(1), 125-134 (1998).|6. Miggin, S.M., Lawler, O.A., and Kinsella, B.T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. 278(9), 6947-6958 (2003).

Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013). Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3 References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013).

ARL67156 (FPL 67156) trisodium hydrate is a selective ecto-ATPase inhibitor. ARL67156 trisodium hydrate is a competitive inhibitor of NTPDase1 (CD39), NTPDase3 and NPP1, with K i s of 11, 18 and 12 μM, respectively. ARL67156 trisodium hydrate can be used in the research of disease like calcific aortic valve disease, asthma [1] [2] .

SAR502250 is a potent, selective, ATP-competitive, orally active, and brain-penetrant GSK3 inhibitor with a human GSK-3β IC50 value of 12 nM. It exhibits antidepressant-like activity and is being researched for potential application in Alzheimer’s disease (AD) treatment.

Palmitic acid-13C is intended for use as an internal standard for the quantification of palmitic acid by GC- or LC-MS. Palmitic acid-13C contains 13C at the C2 position and has been used in the study of free fatty acid incorporation into phospholipid fatty acids in soil microbes.1 Palmitic acid is a 16-carbon saturated fatty acid. It comprises approximately 25% of human total plasma lipids.2 It increases protein levels of COX-2 in RAW 264.7 cells when used at a concentration of 75 μM.3 Palmitic acid is involved in the acylation of proteins to anchor membrane-bound proteins to the lipid bilayer.3,4,5,6,7 |1. Dippold, M.A., and Kuzyakov, Y. Direct incorporation of fatty acids into microbial phospholipids in soils: Position-specific labeling tells the story. Geochim. Cosmochim. Acta 174(1), 211-221 (2016).|2. Santos, M.J., López-Jurado, M., Llopis, J., et al. Influence of dietary supplementation with fish oil on plasma fatty acid composition in coronary heart disease patients. Ann. Nutr. Metab. 39(1), 52-62 (1995).|3. Lee, J.Y., Sohn, K.H., Rhee, S.H., et al. Saturated fatty acids, but not unsaturated fatty acids, induced the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J. Biol. Chem. 276(20), 16683-16689 (2001).|4. Dietzen, D.J., Hastings, W.R., and Lublin, D.M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270(12), 6838-6842 (1995).|5. Robinson, L.J., and Michel, T. Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc. Nat. Acad. Sci. USA 92(25), 11776-11780 (1995).|6. Topinka, J.R., and Bredt, D.S. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 20(1), 125-134 (1998).|7. Miggin, S.M., Lawler, O.A., and Kinsella, B.T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. 278(9), 6947-6958 (2003).

Majoranaquinone demonstrates potent antibacterial activity against four Staphylococcus strains, one Moraxella strain, and one Enterococcus strain. It also acts as an effective efflux pump inhibitor in Escherichia coli ATCC 25922 and inhibits biofilm formation on both E. coli ATCC 25922 and E. coli K-12 AG100 [1].

MTP 131 is a mitochondria-targeted peptide antioxidant.1,2It localizes to the mitochondria and reducestert-butyl hydroperoxide-induced lipid peroxidation and apoptosis in SH-SY5Y cells when used at concentrations ranging from 0.001 to 1 nM.1MTP 131 (2 mg/kg) reduces infarct volume, hemispheric swelling, and glutathione (GSH) depletion in a mouse model of acute cerebral ischemia induced by middle cerebral artery occlusion (MCAO).2It increases survival, improves motor function, and decreases degeneration of the lumbar spinal cord in a superoxide dismutase 1 mutant (SOD1G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS) when administered at a dose of 5 mg/kg. MTP 131 reduces albuminuria, urinary hydrogen peroxide levels, and mesangial matrix accumulation, as well as preserves superoxide production, in adb/dbmouse model of diabetic nephropathy.3 1.Zhao, K., Luo, G., Giannelli, S., et al.Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell linesBiochem. Pharmacol.70(12)1796-1806(2005) 2.Szeto, H.H.Mitochondria-targeted peptide antioxidants: Novel neuroprotective agentsAAPS J.8(3)E521-E531(2006) 3.Miyamoto, S., Zhang, G., Hall, D., et al.Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney diseaseJ. Biol. Chem.295(21)7249-7260(2020)

Nocardamine is a ferrioxamine siderophore that has been found inStreptomycesand has diverse biological activities.1,2,3,4It chelates iron in a chrome azurol S assay (IC50= 9.9 μM).1Nocardamine inhibitsM. smegmatisandM. bovisbiofilm formation (MIC = 10 μM for both), an effect that can be reversed by iron.2It is cytotoxic to T47D, SK-MEL-5, SK-MEL-28, and RPMI-7951 cancer cells (IC50s = 6, 18, 12, and 14 μM, respectively).3Nocardamine also induces morphological changes in BM-N4 insect cells.4 1.Lopez, J.A.V., Nogawa, T., Futamura, Y., et al.Nocardamin glucuronide, a new member of the ferrioxamine siderophores isolated from the ascamycin-producing strain Streptomyces sp. 80H647J. Antibiot. (Tokyo)72(12)991-995(2019) 2.Ishida, S., Arai, M., Niikawa, H., et al.Inhibitory effect of cyclic trihydroxamate siderophore, desferrioxamine E, on the biofilm formation of Mycobacterium speciesBiol. Pharm. Bull.34(6)917-920(2011) 3.Kalinovskaya, N.I., Romaneko, L.A., Irisawa, T., et al.Marine isolate Citricoccus sp. KMM 3890 as a source of a cyclic siderophore nocardamine with antitumor activityMicrobiol. Res.166(8)654-661(2011) 4.Matsubara, K., Sakuda, S., Tanaka, M., et al.Morphological changes in insect BM-N4 cells induced by nocardamineBiosci. Biotechnol. Biochem.62(10)2049-2051(1998)

1. Talatisamine (12 μM) and TEA (5mM) inhibits the enhanced I(K) caused by Aβ4 oligomers, attenuates cytotoxicity of Aβ oligomers by restoring cell viability and suppressing K(+) loss related apoptotic response. 2. Talatisamine can therefore be considered

Heronapyrrole B is a farnesylated 2-nitropyrrole bacterial metabolite that has been found inStreptomycesand has antibacterial activity.1,2It is active against the Gram-positive bacteriaS. aureusandB. subtilis(MICs = 1.8 and 7.5 μM, respectively) but not Gram-negativeP. aeruginosaorE. coli.1 1.Raju, R., Piggott, A.M., Diaz, L.X.B., et al.Heronapyrroles A-C: farnesylated 2-nitropyrroles from an Australian marine-derived Streptomyces spOrg. Lett.12(22)5158-5161(2010) 2.Matsuo, T., Hashimoto, S., Nishikawa, K., et al.Total synthesis and complete stereochemical assignment of heronapyrroles A and BTetrahedron Letters565345-5348(2015)

12-methyl Myristic acid methyl ester is a methylated fatty acid methyl ester that has been found in vermicomposts of cattle manure, carica papaya leaves, and cuticular wax of K. africana. It is a volatile compound in lipid-lowering granulated tea. Levels of 12-methyl myristic acid methyl ester are decreased in T. cruzi treated with nifurtimox compared to non-treated controls.

CDD-1733 is a potent, non-covalent, and non-peptide inhibitor of the SARS-CoV-2 main protease (Mpro) with an inhibition constant (K i) of 12 nM. It effectively inhibits Mpro variants including ΔP168, A173V, and the combined ΔP168/A173V [1].

Mcl-1 Inhibitor 12 (Example 10), with a K i of 0.22 nM, functions as an MCL-1 inhibitor. It is utilized in cancer research [1].

AZT triphosphate TFA (3'-Azido-3'-deoxythymidine-5'-triphosphate TFA) is a active triphosphate metabolite of Zidovudine (AZT). AZT triphosphate TFA exhibits antiretroviral activity and inhibits replication of HIV. AZT triphosphate TFA also inhibits the DNA polymerase of HBV. AZT triphosphate TFA activates the mitochondria-mediated apoptosis pathway[1][2][3]. Treatment with 100 μM Zidovudine (AZT) for 48h disrupts the mitochondrial tubular network via accumulation of AZT triphosphate (AZT-TP) in H9c2 cells. AZT triphosphate accumulation causes downregulation of Opa1 and upregulation of Drp1. AZT triphosphate causes mitochondrial dysfunction, increases the production of cytotoxic reactive oxygen species (ROS), and impairs the balance of the mitochondrial quality control system in H9c2 cell model established from rat embryonic myoblasts[1]. [1]. Ryosuke Nomura, et al. Azidothymidine-triphosphate Impairs Mitochondrial Dynamics by Disrupting the Quality Control System. Redox Biol. 2017 Oct;13:407-417. [2]. Takeya Sato, et al. Engineered Human tmpk/AZT as a Novel Enzyme/Prodrug Axis for Suicide Gene Therapy. Mol Ther. 2007 May;15(5):962-70. [3]. K Y Hostetler, et al. Enhanced Oral Absorption and Antiviral Activity of 1-O-octadecyl-sn-glycero-3-phospho-acyclovir and Related Compounds in Hepatitis B Virus Infection, in Vitro. Biochem Pharmacol. 1997 Jun 15;53(12):1815-22.

β-Defensin-2 is a peptide with antimicrobial properties that protects the skin and mucosal membranes of the respiratory, genitourinary, and gastrointestinal tracts.1It inhibits the growth of periodontopathogenic and cariogenic bacteria, includingP. gingivalisandS. salivarius.2β-Defensin-2 (30 μg/ml) stimulates gene expression and production of IL-6, IL-10, CXCL10, CCL2, MIP-3α, and RANTES by keratinocytes.3It also stimulates calcium mobilization, migration, and proliferation of keratinocytes when used at concentrations of 30, 10, and 40 μg/ml, respectively. β-Defensin-2 induces IL-31 production by human peripheral blood-derived mast cellsin vitrowhen used at a concentration of 10 μg/ml and by rat mast cellsin vivofollowing a 500 ng intradermal dose.4Expression of β-defensin-2 is increased in psoriatic skin and chronic wounds.5,6 1.Lehrer, R.I.Primate defensinsNat. Rev. Microbiol.2(9)727-738(2004) 2.Ouhara, K., Komatsuzawa, H., Yamada, S., et al.Susceptibilities of periodontopathogenic and cariogenic bacteria to antibacterial peptides, β-defensins and LL37, produced by human epithelial cellsJ. Antimicrob. Chemother.55(6)888-896(2005) 3.Niyonsaba, F., Ushio, H., Nakano, N., et al.Antimicrobial peptides human β-defensins stimulate epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokinesJ. Invest. Dermatol.127(3)594-604(2007) 4.Niyonsaba, F., Ushio, H., Hara, M., et al.Antimicrobial peptides human β-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cellsJ. Immunol.184(7)3526-3534(2010) 5.Huh, W.-K., Oono, T., Shirafuji, Y., et al.Dynamic alteration of human β-defensin 2 localization from cytoplasm to intercellular space in psoriatic skinJ. Mol. Med. (Berl.)80(10)678-684(2002) 6.Butmarc, J., Yufit, T., Carson, P., et al.Human β-defensin-2 expression is increased in chronic woundsWound Repair Regen.12(4)439-443(2004)

Gliovirin is a fungal metabolite that has been found inT. harzianumand has fungicidal, antimicrobial and anti-inflammatory activities.1It is active against the plant pathogenic fungusP. ultimum(MIC = 60 ng/ml) and the parasiteT. brucei brucei(IC50= 90 ng/ml), but has no effect on the plant pathogenic fungiR. solani,P. omnivorum,T. basicola,R. arrhizus, andV. dahliaeor the bacteriaB. thuringiensis,P. fluorescens, andX. malvacearumwhen used at concentrations up to 1,000 ng/ml.2,3Gliovirin decreases phorbol 12-myristate 13-acetate (TPA)- and ionomycin-induced increased expression of COX-2 (IC50= 1 μM) and protein levels of IL-2 in Jurkat cells (IC50= 5.2 μM).1 1.Rether, J., Serwe, A., Anke, T., et al.Inhibition of inducible tumor necrosis factor-α expression by the fungal epipolythiodiketopiperazine gliovirinBiol. Chem.388(6)627-637(2007) 2.Howell, C.R., and Stipanovic, R.D.Gliovirin, a new antibiotic from Gliocladium virens, and its role in the biological control of Pythium ultimumCan. J. Microbiol.29(3)321-324(1983) 3.Iwatsuki, M., Otoguro, K., Ishiyama, A., et al.In vitro antitrypanosomal activity of 12 low-molecular-weight antibiotics and observations of structure/activity relationshipsJ. Antibiot. (Tokyo)63(10)619-622(2010)

Colletodiol is a fungal metabolite that has been found inD. grovesiiand has immunosuppressant and antiviral activities.1,2It inhibits concanavalin A- or LPS-induced proliferation of isolated mouse splenocytes (IC50s = 12 and 5 μg/ml, respectively).1Colletodiol inhibits influenza A viral replication in HeLa-IAV-Luc cells.2 1.Fujimoto, H., Nagano, J., Yamaguchi, K., et al.Immunosuppressive components from an ascomycete, Diplogelasinospora grovesiChem. Pharm. Bull.46(3)423-429(1998) 2.Lai, W., Wang, S., and Ye, X.Colletodiol inhibits the replication of influenza A virus WSN/H1N1 by reducing the activity of viral RNA polymeraseWei Sheng Wu Xue Bao53(12)1334-1339(2013)

Eicosapentaenoic acid (EPA) is metabolized into epoxyeicosatetraenoic acids (EpETE) by multiple cytochrome P450 isoforms. The predominant compound of this epoxygenase pathway, (±)17(18)-EpETE, induces relaxation in vascular and airway smooth muscles through its action on large conductance Ca2+-activated K+ (BKCa) channels, specifically by binding to the BKα channel subunits. Another notable epoxygenase pathway derivative, (±)11(12)-EpETE, also generated from EPA via CYP450 activity in both in vitro and in vivo studies, has biological and physiological roles that are yet to be fully elucidated.

Retigabine-d4 is a deuterated compound of Retigabine. Retigabine has a CAS number of 150812-12-7. Retigabine dihydrochloride is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The mechanism of action involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels.

4-Amino-6-chloro-1,3-benzenedisulfonamide is a carbonic anhydrase inhibitor.1 Formulations containing this compound are diuretics.2 4-Amino-6-chloro-1,3-benzenedisulfonamide is detected as a hydrolysis product of chlorothiazide in the urine.2 Diuretics, including chlorothiazide, have been abused as performance-enhancing drugs and masking agents in sports doping.3References1. Nishimori, I., Vullo, D., Minakuchi, T., et al. Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pylori. Bioorg. Med. Chem. Lett. 16(8), 2182-2188 (2006).2. Deventer, K., Pozo, O.J., Van Eenoo, P., et al. Detection of urinary markers for thiazide diuretics after oral administration of hydrochlorothiazide and altizide-relevance to doping control analysis. J. Chromatogr. A 1216(12), 2466-2473 (2009).3. Cadwallader, A.B., de la Torre, X., Tieri, A., et al. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: Pharmacology, toxicology and analysis. Br. J. Pharmacol. 161(1), 1-16 (2010). 4-Amino-6-chloro-1,3-benzenedisulfonamide is a carbonic anhydrase inhibitor.1 Formulations containing this compound are diuretics.2 4-Amino-6-chloro-1,3-benzenedisulfonamide is detected as a hydrolysis product of chlorothiazide in the urine.2 Diuretics, including chlorothiazide, have been abused as performance-enhancing drugs and masking agents in sports doping.3 References1. Nishimori, I., Vullo, D., Minakuchi, T., et al. Carbonic anhydrase inhibitors: Cloning and sulfonamide inhibition studies of a carboxyterminal truncated α-carbonic anhydrase from Helicobacter pylori. Bioorg. Med. Chem. Lett. 16(8), 2182-2188 (2006).2. Deventer, K., Pozo, O.J., Van Eenoo, P., et al. Detection of urinary markers for thiazide diuretics after oral administration of hydrochlorothiazide and altizide-relevance to doping control analysis. J. Chromatogr. A 1216(12), 2466-2473 (2009).3. Cadwallader, A.B., de la Torre, X., Tieri, A., et al. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: Pharmacology, toxicology and analysis. Br. J. Pharmacol. 161(1), 1-16 (2010).

TAS-103 is a dual inhibitor of DNA topoisomerase I/II, used for cancer research. TAS-103 is a dual inhibitor of DNA topoisomerase I/II. TAS-103 (0.1-10 μM) is active on CCRF-CEM cells, with an IC50 value of 5 nM. TAS-103 (0.1 μM) significantly increases levels of topo IIα FITC immunofluorescence in individual CCRF-CEM cells[1]. TAS-103 (0.01-1 μM) is highly cytotoxic to Lewis lung carcinoma (LLC) cells, and Liposomal TAS-103 is almost as active as free TAS-103[2]. TAS-103 inhibits the viability of HeLa cells, with an IC50 of 40 nM. TAS-103 (10 μM) disrupts signal recognition particle (SRP) complex formation, and induces destabilization of SRP14 and SRP19 and its eventual degradation[3]. TAS-103 (30 mg/kg, i.v.) causes significant tumor growth suppression in mice bearing Lewis lung carcinoma (LLC) cells, without obvious body weight loss, and the liposomal TAS-103 is more active than free TAS-103[2]. [1]. Padget K, et al. An investigation into the formation of N- [2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and 6-[2-(dimethylamino)ethylamino]- 3-hydroxy-7H-indeno[2, 1-C]quinolin-7-one dihydrochloride (TAS-103) stabilised DNA topoisomerase I and II cleavable complexes in human leukaemia cells. Biochem Pharmacol. 2000 Sep 15;60(6):817-21. [2]. Shimizu K, et al. Cancer chemotherapy by liposomal 6-[12-(dimethylamino)ethyl]aminol-3-hydroxy-7H-indeno[2,1-clquinolin-7-one dihydrochloride (TAS-103), a novel anti-cancer agent. Biol Pharm Bull. 2002 Oct;25(10):1385-7. [3]. Yoshida M, et al. A new mechanism of 6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one dihydrochloride (TAS-103) action discovered by target screening with drug-immobilized affinity beads. Mol Pharmacol. 2008 Mar;73(3):987-94. Epub 2007 Dec 18.

Cytosolic phospholipase A2α (cPLA2α) specifically catalyzes the hydrolysis of arachidonic acid from thesn-2-ester position of membrane phospholipids, playing a central role in initiating the synthesis of prostaglandins and leukotrienes, both important mediators of the inflammatory process.1CAY10641 is an inactive alcohol derivative of a highly potent (IC50= 12 nM) cPLA2α inhibitor.2The parent compound demonstrates strong anti-inflammatory effects when applied topically at a dose of 0.1 mg/ear in a mouse model of acute irritant contact dermatitis.2CAY10641 is rapidly cleared from the blood stream (only 0.5 μg/ml remains 30 minutes after 10 mg/kg intravenous administration to mice).2However, no other biological effects have been reported. 1.Schaloske, R.H., and Dennis, E.A.The phospholipase A2 superfamily and its group numbering systemBiochemica et Biophysica Acta17611246-1259(2006) 2.Drews, A., Bovens, S., Roebrock, K., et al.1-(5-carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A2α with reduced lipophilicity: Synthesis, biological activity, metabolic stability, solubility, bioavailability, and topical in vivo activityJournal of Medicinal Chemistry535165-5178(2010)

Alaproclate is a selective serotonin reuptake inhibitor (SSRI).1,2 It inhibits depletion of serotonin (5-HT) induced by 4-methyl-α-ethyl-m-tyramine in rat cerebral cortex, hippocampus, hypothalamus, and striatum (EC50s = 18, 4, 8, and 12 mg/kg, respectively).1 Alaproclate inhibits NMDA-evoked currents and depolarization-induced voltage-dependent potassium currents in rat hippocampal neurons (IC50s = 1.1 and 6.9 μM, respectively) and does not inhibit GABA-evoked currents when used at concentrations up to 100 μM.2 It increases sirtuin 1 (SIRT1) levels in N2a murine neuroblastoma cells expressing apolipoprotein E4 (ApoE4; IC50 = 2.3 μM) and in the hippocampus in the FXFAD-ApoE4 transgenic mouse model of Alzheimer's disease when administered at a dose of 20 mg/kg twice daily.3 Alaproclate (40 mg/kg) decreases immobility time in the forced swim test in rats, indicating antidepressant-like activity.4References1. Michael, G.B., Eidam, C., Kadlec, K., et al. Increased MICs of gamithromycin and tildipirosin in the presence of the genes erm(42) and msr(E)-mph(E) for bovine Pasteurella multocida and Mannheimia haemolytica. Journal of Antimicrobial Chemotherapy 67(6), 1555-1557 (2012).2. Svensson, B.E., Werkman, T.R., and Rogawski, M.A. Alaproclate effects on voltage-dependent K+ channels and NMDA receptors: Studies in cultured rat hippocampal neurons and fibroblast cells transformed with Kv1.2 K+ channel cDNA. Neuropharmacology 33(6), 795-804 (1994).3. Campagna, J., Soilman, P., Jagodzinska, B., et al. A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model. Sci. Rep. 8(1), 17574 (2018).4. Danysz, W.P., A., Kostowski, W., Malatynska, E., et al. Comparison of desipramine, amitriptyline, zimeldine and alaproclate in six animal models used to investigate antidepressant drugs. Pharmacol. Toxicol. 62(1), 42-50 (1988). Alaproclate is a selective serotonin reuptake inhibitor (SSRI).1,2 It inhibits depletion of serotonin (5-HT) induced by 4-methyl-α-ethyl-m-tyramine in rat cerebral cortex, hippocampus, hypothalamus, and striatum (EC50s = 18, 4, 8, and 12 mg/kg, respectively).1 Alaproclate inhibits NMDA-evoked currents and depolarization-induced voltage-dependent potassium currents in rat hippocampal neurons (IC50s = 1.1 and 6.9 μM, respectively) and does not inhibit GABA-evoked currents when used at concentrations up to 100 μM.2 It increases sirtuin 1 (SIRT1) levels in N2a murine neuroblastoma cells expressing apolipoprotein E4 (ApoE4; IC50 = 2.3 μM) and in the hippocampus in the FXFAD-ApoE4 transgenic mouse model of Alzheimer's disease when administered at a dose of 20 mg/kg twice daily.3 Alaproclate (40 mg/kg) decreases immobility time in the forced swim test in rats, indicating antidepressant-like activity.4 References1. Michael, G.B., Eidam, C., Kadlec, K., et al. Increased MICs of gamithromycin and tildipirosin in the presence of the genes erm(42) and msr(E)-mph(E) for bovine Pasteurella multocida and Mannheimia haemolytica. Journal of Antimicrobial Chemotherapy 67(6), 1555-1557 (2012).2. Svensson, B.E., Werkman, T.R., and Rogawski, M.A. Alaproclate effects on voltage-dependent K+ channels and NMDA receptors: Studies in cultured rat hippocampal neurons and fibroblast cells transformed with Kv1.2 K+ channel cDNA. Neuropharmacology 33(6), 795-804 (1994).3. Campagna, J., Soilman, P., Jagodzinska, B., et al. A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer's disease mouse model. Sci. Rep. 8(1), 17574 (2018).4. Danysz, W.P., A., Kostowski, W., Malatynska, E., et al. Comparison of desipramine, amitriptyline, zimeldine and alaproclate in six animal models used to investigate antidepressant drugs. Pharmacol. Toxicol. 62(1), 42-50 (1988).

Bovine tracheal antimicrobial peptide, derived from the tracheal mucosa, exhibits antimicrobial efficacy against E. coli D31, K. pneumoniae 13883, S. aureus 25923, P. aeruginosa 27853, and C. albicans 14053, with respective minimum inhibitory concentration (MIC) values ranging from 12-25 μg/ml for the first two pathogens, 25-50 μg/ml for the following two, and 6-12 μg/ml for the latter [1].

Spiro-oxanthromicin A is a polyketide that has been found inStreptomyces.1It induces mislocalization of K-RAS in MDCK cells (IC50= 26.7 μM). 1.Salim, A.A., Xiao, X., Cho, K.J., et al.Rare Streptomyces sp. polyketides as modulators of K-Ras localisationOrg. Biomol. Chem.12(27)4872-4878(2014)

Enpp-1-IN-12 (compound 43), an orally active and potent inhibitor of ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1) with a K i of 41 nM, exhibits anti-tumor activity [1].

Proteinase K (proteinase K for tritirachium album) is a nonspecific serine protease that is useful for general digestion of proteins. It is active in the presence of SDS or urea and over a wide range of pH (4-12), salt concentrations, and temperatures.