https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:12632 Wed 11 Apr 2018 13:22:57 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53392 Thu 23 Nov 2023 13:37:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33408 Thu 04 Nov 2021 10:39:25 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19179 Sat 24 Mar 2018 07:52:17 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:55677 H)-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 64 and 2-(3-methoxystyryl)quinazolin-4(3H)-one 65 and 2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one 39 exhibited sub-μM potency growth inhibition values. Of these 1-naphthyl 39 has 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 50 docked 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 43 and 47 were modest promotors of tubulin polymerisation, but less effective than paclitaxel. Analogues 39, 64, and 65 showed reduced microtubule formation consistent with tubulin inhibition. The variation in ring methoxy substituent with 50, 64 and 65, from o- to m- to p-, results in a concomitant reduction in cytotoxicity and a reduction in tubulin polymerisation, with p-OCH₃50 being the least active in this series of analogues. This presents 64 as 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 39 and 64 induced G₂ + M cell cycle arrest indicative of inhibition of tubulin polymerisation, with 39 inducing an equivalent effect on cell cycle arrest as nocodazole (68).]]> Mon 17 Jun 2024 10:11:24 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49507 Fri 19 May 2023 16:35:01 AEST ]]>