3216-88-4

A synthesis of bis(dihydropyridine-3,5-dicarbonitrile) by a three-component reaction of one equivalent of bis-cyanoacetamides with two equivalents of both arylaldehydes and malononitrile in ethanol-containing piperidine is reported. Bis-cyanopyridones could also be obtained by the condensation of bis-cyanoacetamides with substituted arylidenemalononitriles in the presence of piperidine, chitosan, or montmorillonite as basic catalysts. The cytotoxicity of the synthesized products against the heterogeneous human epithelial colorectal adenocarcinoma cell line (Caco-2) was assessed by WST-1 assay with concentration dependent cellular growth inhibitory effect especially for compounds 5l, 5h, and 5d. The dose response curves indicate that IC50 were 87?±?3.11?μg/mL, 104?±?4.78?μg/mL, and 108?±?5.12?μg/mL, respectively.

Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a ìèpotent lead, 2-cyano-3-(3,4- dihydroxyphenyl)thioacrylamide (1, IC50 70 μM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low μM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50 = 5.1 ± 0.6 μM), its 3,4,5-trihydroxy congener (10) (IC50 = 1.7 ± 0.2 μM), and the corresponding 3-methyl ether (11) (IC 50 = 9 ± 3 μM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50's of 1.7 ± 0.2, 1.7 ± 0.2, and 5 ± 1 μM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50's of 42 ± 3, 38 ± 2, and 61 ± 2 μM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.

The combination of semi-automation, an elegant synthesis, and parallel solution-phase synthesis approaches has allowed the development of five targeted, symmetrical tyrphostin compound libraries. These libraries on average are comprised of 12 compounds. Notwithstanding this, low micromolar potent growth inhibitors against HT29 (colorectal carcinoma) and G401 (renal carcinoma) cell lines were discovered. Additionally, significant SAR data was obtained. We noted that the most potent growth inhibitory activity was consistently observed for those analogues that possessed a 2-chlorophenyl (for 10: GI 50HT29 5.5 ± 0.4 μM, GI50G401 2.6 ± 0.4 μM; for 23: GI50HT29 2.4 ± 0.2 μM, GI50G401 1.9 ± 1 μM; for 34: GI50HT29 8.8 ± 3.1 μM. GI50G401 6.2 ± 2.9 μM; for 46: GI50HT29 5.2 ± 0.9 μM, GI50G401 3.7 ± 0.6 μM; for 57: GI 50HT29 4.6 ± 0.8 μM, GI50G401 2.1 ± 0.2 μM), a 3-chlorophenyl (for 11: GI50HT29 3.8 ± 0.7 μM, GI50G401 1.7 ± 0.7 μM; for 48: GI50HT29 5.9 ± 0.1 μM, GI50G401 3.4 ± 0.6 μM; for 58: GI 50HT29 4.8 ± 0.9 μM, GI50G401 3.4 ± 0.2 μM), or a 3-methoxyphenyl substituent (for 13: GI50HT29 7.4 ± 3.8 μM, GI50G401 2.8 ± 0.5 μM; for 26: GI 50HT29 4.5 ± 0.5 μM, GI50G401 4.9 ± 1 μM; for 37: GI50HT29 3.7 ± 0.2 μM, GI50G401 1.6 ± 0.2 μM; for 49: GI50HT29 3.7 ± 0.4 μM, GI50G401 3.4 ± 0.2 μM; for 60: GI50HT29 4.1 ± 0.6 μM, GI50G401 1.8 ± 0.3 μM). Finally, we noted that increasing the distance between the terminal aromatic rings had only a minimal effect on the 2-, 3-chlorophenyl, and 3-methoxyphenyl analogues, but did have a favourable effect on OH, COOH, and multiply substituted analogues. CSIRO 2005.

There are disclosed methods for inhibiting dynamin-dependent endocytosis in cells comprising treating the cells with an effective amount of a compound of formula (I), or a dimeric tyrphostin, physiologically acceptable salt, or prodrug thereof. Compounds useful in the methods described are also provided. The inhibition of dynamin-dependent endocytosis of cells is applicable to the treatment of epilepsy and neurological disorders and conditions

A preparation of bis-lactams is described from α-ketols and bis- cyanamides in the presence of sodium ethoxide at room temperature. One of these compounds leads to an unsaturated derivative by condensation with furfural, or to a saturated analogue via catalytic hydrogenation.

Benzylidenemalononitrile (BMN) tyrphostins were previously found to be potent inhibitors of EGF receptor (EGFR) tyrosine kinase activity. Since these compounds were found to compete for the substrate and sometimes with the ATP site and since EGFR acts as a dimer, we prepared a series of dimeric tyrphostins. These dimeric tyrphostins were built from two BMN units linked by various spacers and designed to fit the dimeric cross-autophosphorylation signal transduction intermediate of the EGFR tyrosine kinases. Structure- activity relationship of these potent dimeric EGF receptor tyrosine kinase inhibitors is reported.