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Tubulin plays a central role in mitosis and has been the target of multiple anticancer drugs, including paclitaxel. Herein two separate families of 2,3-dihydroquinazoline-4(1H)-ones and quinazoline-4(3H) ones, comprising 57 compounds in total, were synthesised. Screening against a broad panel of human cancer cell lines (HT29 colon, U87 and SJ-G2 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, and MIA pancreas) reveals these analogues to be broad spectrum cytotoxic compounds. Of particular note, 2-styrylquinazolin-4(3H)-one 51, 2-(4-hydroxystyryl)quinazolin-4(3H)-one 63, 2-(2-methoxystyryl)quinazolin-4(3H)-one 64and 2-(3-methoxystyryl)quinazolin-4(3H)-one 65and 2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one 39exhibited sub-μM potency growth inhibition values. Of these 1-naphthyl 39has activity <50 nM against the HT29, U87, A2780, H460 and BE2-C cell lines. Molecular modelling of these compounds, e.g.2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one 39, 2-(2-methoxystyryl)quinazolin-4(3H)-one 64, 2-(3-methoxystyryl)quinazolin-4(3H)-one 65, and 2-(4-methoxystyryl)quinazolin-4(3H)-one 50docked to the known tubulin polymerisation inhibitor sites highlighted well conserved interactions within the colchicine binding pocket. These compounds were examined in a tubulin polymerisation assay alongside the known tubulin polymerisation promotor, paclitaxel (69), and tubulin inhibitor, nocodazole (68). Of the analogues examined, indoles 43and 47were modest promotors of tubulin polymerisation, but less effective than paclitaxel. Analogues 39, 64, and 65showed reduced microtubule formation consistent with tubulin inhibition. The variation in ring methoxy substituent with 50, 64and 65, from o- to m- to p-, results in a concomitant reduction in cytotoxicity and a reduction in tubulin polymerisation, with p-OCH350being the least active in this series of analogues. This presents 64as a tubulin polymerisation inhibitor possessing novel chemotype and sub micromolar cytotoxicity. Naphthyl 39, with complete inhibition of tubulin polymerisation, gave rise to a sub 0.2 μM cell line cytotoxicity. Compounds 39and 64induced G2+ M cell cycle arrest indicative of inhibition of tubulin polymerisation, with 39inducing an equivalent effect on cell cycle arrest as nocodazole (68).

From lead 1, (N-(4-((4-(3-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2–p53 protein–protein interaction inhibitor based on an in silicomodelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against 16 human cancer cell lines including the pancreatic cell lines MiaPaCa2, BxPC3, AsPC-1, Capan-2, HPAC, PANC-1 and the drug resistant CFPAC1. Modification of 1’s phenylacetamide moiety, gave Library 1with only modest pancreatic cancer activity. Modification of the 3-OCH3Ph moiety (Library 2) gave 4-CH3(26), 4-CH2CH3(27), 4-CF3(31) and 4-NO2(32) with sterically bulky groups more active. A 4-CF3acetamide replacement enhanced cytotoxicity (Library 3). The 4-C(CH3)336resulted in a predicted steric clash in the S100A2–p53 binding groove, with a potency decrease. Alkyl moieties afforded more potent analogues, 34(4-CH3) and 35(CH2CH3), a trend evident against pancreatic cancer: GI503.7 (35; BxPC-3) to 18 (40; AsPC-1) μM. Library 4analogues with a 2-CF3and 3-CF3benzenesulfonamide moiety were less active than the corresponding Library 3analogues. Two additional analogues were designed: 51(4-CF3; 4-OCH3) and 52(4-CF3; 2-OCH3) revealed 52to be 10–20 fold more active than 51, against the pancreatic cancer cell lines examined with sub-micromolar GI50values 0.43 (HPAC) to 0.61 μM (PANC-1). MOE calculated binding scores for each pose are also consistent with the observed biological activity with 52. The obtained SAR data is consistent with the proposed interaction within the S100A2–p53 bonding groove.