1v-136

Pevonedistat (MLN4924) is a potent and selective NEDD8 activating enzyme (NAE) inhibitor (IC50=4.7 nM) with therapeutic potential for myelodysplastic syndromes (MDS) and antitumor activity.

Dulcite (D-Galactitol) is a sugar alcohol that is a metabolic breakdown product of galactose.

Usnic Acid (Usniacin) is an antimicrobial, antitumor and enzyme inhibiting agent shown to uncouple oxidative phosphorylation in mouse-liver mitochondria. Usnic acid induces necrosis in certain cells.

Oxaloacetic acid, also known as oxosuccinic acid or oxalacetic acid, is a four-carbon dicarboxylic acid appearing as an intermediate of the citric acid cycle. In vivo, oxaloacetate (the ionized form of oxaloacetic acid) is formed by the oxidation of L-mal

KEAP1-NRF2PPI-IN-1 (compound 23) is an inhibitor targeting the KEAP1-NRF2 interaction. In DNA damage tests, its IC50 values are 136 nM in human TK6 cell lines and 62 nM in insect SF9 cell lines.

UMB-136 is a bromodomain BRD4 inhibitor that acts by significantly inducing HIV-1 reactivation.

NLCQ-1 is a novel weak DNA-intercalative bioreductive compound. NLCQ-1 exhibited a C50 of 44 microM. NLCQ-1 demonstrated significant hypoxic selectivity in several rodent (V79, EMT6, SCCVII) or human (A549, OVCAR-3) tumor cell lines. Its potency as a hypo

(±)10-HDHA is an autoxidation product of docosahexaenoic acid (DHA) in vitro.[1][2] It is also produced from incubations of DHA in rat liver, brain, and intestinal microsomes.[3][4][5] (±)10-HDHA is a potential marker of oxidative stress in brain and retina where DHA is an abundant polyunsaturated fatty acid. Reference:[1]. VanRollins, M., and Murphy, R.C. Autooxidation of docosahexaenoic acid: Analysis of ten isomers of hydroxydocosahexaenoate. J. Lipid Res. 25(5), 507-517 (1984).[2]. Reynaud, D., Thickitt, C.P., and Pace-Asciak, C.R. Facile preparation and structural determination of monohydroxy derivatives of docosahexaenoic acid (HDoHE) by α-tocopherol-directed autoxidation. Anal. Biochem. 214(1), 165-170 (1993).[3]. VanRollins, M., Baker, R.C., Sprecher, H., et al. Oxidation of docosahexaenoic acid by rat liver microsomes. J. Biol. Chem. 259(9), 5776-5783 (1984).[4]. Yamane, M., Abe, A., and Yamane, S. High-performance liquid chromatography-thermospray mass spectrometry of epoxy polyunsaturated fatty acids and epoxyhydroxy polyunsaturated fatty acids from an incubation mixture of rat tissue homogenate. J. Chromatogr. 652(2), 123-136 (1994).[5]. Kim, H.Y., Karanian, J.W., Shingu, T., et al. Sterochemical analysis of hydroxylated docosahexaenoates produced by human platelets and rat brain homogenate. Prostaglandins 40(5), 473-490 (1990).

Ajoene is a disulfide that has been found inA. sativumand has diverse biological activities, including antibacterial, anticancer, antiplatelet, and antioxidant properties.1,2,3,4It is active against Gram-positive (MICs = 5-160 µg/ml) and Gram-negative bacteria (MICs = 136-200 µg/ml), as well as yeasts (MICs = 10-20 µg/ml).1Ajoene is cytotoxic to mouse melanoma cells (IC50= 18 µM), as well as human colon, lung, mammary, and pancreatic cancer cells (IC50s = 7-41 µM).2It reduces tumor growth in a B16/BL6 mouse model of melanoma when administered at a dose of 25 mg/kg every other day and decreases the number of lung metastases when administered prior to tumor cell inoculation at doses ranging from 1-25 mg/kg. It inhibits ADP- or collagen-induced platelet aggregation in isolated baboon platelets when used at concentrations ranging from 75 to 150 µg/ml and in platelet-rich plasma isolated from baboons when administered at a dose of 25 mg/kg.3Ajoene (25 mg/kg) prevents thrombus formation on damaged arterial walls in heparinized pigs in anin situmodel of thrombogenesis.5It also reduces high-fat diet-induced hepatic steatosis, histopathological markers of liver damage, thiobarbituric acid reactive substances (TBARS) formation, and protein oxidation in a mouse model of non-alcoholic fatty liver disease (NAFLD).4 1.Naganawa, R., Iwata, N., Ishikawa, K., et al.Inhibition of microbial growth by ajoene, a sulfur-containing compound derived from garlicAppl. Environ. Microbiol.62(11)4238-4242(1996) 2.Taylor, P., Noriega, R., Farah, C., et al.Ajoene inhibits both primary tumor growth and metastasis of B16/BL6 melanoma cells in C57BL/6 miceCancer Lett.239(2)298-304(2006) 3.Teranishi, K., Apitz-Castro, R., Robson, S.C., et al.Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoeneXenotransplantation10(4)374-379(2003) 4.Han, C.Y., Ki, S.H., Kim, Y.W., et al.Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activationAntioxid. Redox Signal.14(2)187-202(2011) 5.Apitz-Castro, R., Badimon, J.J., and Badimon, L.A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental modelThromb. Res.75(3)243-249(1994)

GLP-1 amide is a peptide hormone cleaved from proglucagon in the pancreas.1,2 Mice lacking the glucagon receptor (Gcgr-/-) have approximately nine-fold higher levels of total GLP-1 amide, including GLP-1 (1-36) amide and truncated GLP-1 (7-36) amide , in pancreatic tissue compared to wild-type mice.2References1. Schjoldager, B.T., Mortensen, P.E., Christiansen, J., et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig. Dis. Sci. 34(5), 703-708 (1989).2. Gelling, R.W., Du, X.Q., Dichmann, D.S., et al. Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 100(3), 1438-1443 (2003). GLP-1 amide is a peptide hormone cleaved from proglucagon in the pancreas.1,2 Mice lacking the glucagon receptor (Gcgr-/-) have approximately nine-fold higher levels of total GLP-1 amide, including GLP-1 (1-36) amide and truncated GLP-1 (7-36) amide , in pancreatic tissue compared to wild-type mice.2 References1. Schjoldager, B.T., Mortensen, P.E., Christiansen, J., et al. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig. Dis. Sci. 34(5), 703-708 (1989).2. Gelling, R.W., Du, X.Q., Dichmann, D.S., et al. Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 100(3), 1438-1443 (2003).

para-amino-Blebbistatin is a more water-soluble form of (S)-4'-nitro-blebbistatin , which is a more stable and less phototoxic form of (-)-blebbistatin .1,2,3 (-)-Blebbistatin is a selective cell-permeable inhibitor of non-muscle myosin II ATPases that rapidly and reversibly inhibits Mg-ATPase activity and in vitro motility of non-muscle myosin IIA and IIB for several species (IC50s = 0.5-5 μM), while poorly inhibiting smooth muscle myosin (IC50 = 80 μM).2,3,4 Through these effects, it blocks apoptosis-related bleb formation, directed cell migration, and cytokinesis in vertebrate cells. However, prolonged exposure to blue light (450-490 nm) results in degradation of blebbistatin to an inactive product via cytotoxic intermediates, which may be problematic for its use in fluorescent live cell imaging applications.5,6 The addition of a 4'-amino group increases its water solubility, decreases the inherent fluorescence, stabilizes the molecule to circumvent its degradation by prolonged blue light exposure, and decreases its phototoxicity while retaining the in vitro and in vivo activity of blebbistatin.7 para-amino-Blebbistatin has the same stereochemistry as the active (-)-blebbistatin enantiomer. |1. Várkuti, B.H., Képiró, M., Horváth, I.á., et al. A highly soluble, non-phototoxic, non-fluorescent blebbistatin derivative. Sci. Rep. 6:26141, (2016).|2. Straight, A.F., Cheung, A., Limouze, J., et al. Dissecting temporal and spatial control of cytokinesis with a myosin II inhibitor. Science 299(5613), 1743-1747 (2003).|3. Kovács, M., Tóth, J., Hetényi, C., et al. Mechanism of blebbistatin inhibition of myosin II. J. Biol. Chem. 279(34), 35557-35563 (2004).|4. Limouze, J., Straight, A.F., Mitchison, T., et al. Specificity of blebbistatin, an inhibitor of myosin II. J. Muscle Res. Cell Motil. 25(4-5), 337-341 (2004).|5. Kolega, J. Phototoxicity and photoinactivation of blebbistatin in UV and visible light. Biochem. Biophys. Res. Commun. 320(3), 1020-1025 (2004).|6. Sakamoto, T., Limouze, J., Combs, C.A., et al. Blebbistatin, a myosin II inhibitor, is photoinactivated by blue light. Biochemistry 44(2), 584-588 (2005).|7. Verhasselt, S., Roman, B.I., Bracke, M.E., et al. Improved synthesis and comparative analysis of the tool properties of new and existing D-ring modified (S)-blebbistatin analogs. Eur. J. Med. Chem. 136, 85-103 (2017).

cDPCP is a platinum-containing DNA-crosslinking agent.1Unlike cisplatin or oxaliplatin , cDPCP forms monofunctional DNA adducts. It is transported into cells by organic cation transporter 1 (OCT1) and OCT2, inhibiting proliferation of MDCK cells expressing the human transporters with IC50values of 8.1 and 1.5 μM, respectively. cDPCP inhibits RNA polymerase II-mediated transcription in a reporter assay using HeLa cells. It increases survival in murine S180 sarcoma and P388 leukemia models when administered at doses of 40 and 80 mg/kg, respectively.2 1.Lovejoy, K.S., Todd, R.C., Zhang, S., et al.cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospectsProc. Natl. Acad. Sci. USA105(26)8902-9807(2008) 2.Hollis, L.S., Amundsen, A.R., and Stern, E.W.Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+J. Med. Chem.32128-136(1989)

Protein Kinase Inhibitors 1 Hydrochloride effectively inhibits HIPK2, demonstrating high potency with IC50 values of 136 nM for HIPK1 and 74 nM for HIPK2, alongside a dissociation constant (Kd) of 9.5 nM for HIPK2.

WSF1-IN-1 (compound 136) is an orally active inhibitor of WSF1, designed for studying WSF1-related tumors in patients with Wolfram syndrome (WS). In HepG2 parental and HepG2 WFS1 KO cell lines, WSF1-IN-1 has shown IC50 values of 0.33 μM and >27 μM, respectively.

Rbin-1 (Ribozinoindole-1) is a potent,specific inhibitor of eukaryotic ribosome biogenesis.

Antibacterial Agent 136 (Compound 3), an oxadiazolone antibiotic, exhibits high antibacterial potency against Methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) 50 value of 0.8 μM [1].

Anticancer agent 136 (compound 22), a C17-triazole analogue of Geldanamycin (GDM), exhibits an IC50 value of 3.38 μM against human dermal fibroblasts (HDF) and binds to Heat shock protein 90 (Hsp90) with a dissociation constant (Kd) of 3.86 μM, demonstrating its apoptosis-inducing capabilities [1].

Tat-Gap 19, a peptide inhibitor of connexin43 (Cx43) hemichannels, is derived from the HIV-1 Tat protein transduction domain fused with a nine-amino acid sequence from Cx43 residues 128-136. This compound, at a concentration of 10 µM, effectively suppresses glutamate-induced ATP release in primary rat hepatocytes, indicating inhibition of Cx43 hemichannel activity. Furthermore, Tat-Gap 19 demonstrates therapeutic potential by significantly reducing infarct volume in a mouse cerebral ischemia-reperfusion injury model following middle cerebral artery occlusion (MCAO) at a dosage of 25 mg/kg. Moreover, its intraperitoneal administration at 1 mg/kg per day ameliorates fibrosis and decreases the area of hepatic stellate cells, the precursors to myofibroblasts, expressing α-smooth muscle actin (α-SMA), in a model of thioacetamide-induced liver damage. Additionally, it enhances superoxide dismutase (SOD) activity in hepatic cells from the treated mice, indicating its antioxidative benefits.

Antitumor Agent-136 (Compound 17), a broad-spectrum antitumor agent and NAMPT inhibitor, exhibits potent activity with an IC50 of 9.5 nM. It efficiently lowers intracellular and extracellular NAMPT protein levels via the ubiquitin proteasome pathway, achieving effective tumor inhibition [1].

BRD4 Inhibitor-31 (Example 136), with inhibition constants (K i s) of 0.234 μM and 0.295 μM for BRD4 BD1 and BRD4 BD2 respectively, serves as a BRD4 inhibitor. It is utilized in the research of inflammatory diseases, cancer, and AIDS [1].