2,3-Dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones as broad-spectrum cytotoxic agents and their impact on tubulin polymerisation

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 <bold>51</bold>, 2-(4-hydroxystyryl)quinazolin-4(3H)-one <bold>63</bold>, 2-(2-methoxystyryl)quinazolin-4(3H)-one <bold>64</bold> and 2-(3-methoxystyryl)quinazolin-4(3H)-one <bold>65</bold> and 2-(naphthalen-1-yl)-2,3-dihydroquinazolin-4(1H)-one <bold>39</bold> exhibited sub-mu M potency growth inhibition values. Of these 1-naphthyl <bold>39</bold> 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 <bold>39</bold>, 2-(2-methoxystyryl)quinazolin-4(3H)-one <bold>64</bold>, 2-(3-methoxystyryl)quinazolin-4(3H)-one <bold>65</bold>, and 2-(4-methoxystyryl)quinazolin-4(3H)-one <bold>50</bold> 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 (<bold>69</bold>), and tubulin inhibitor, nocodazole (<bold>68</bold>). Of the analogues examined, indoles <bold>43</bold> and <bold>47</bold> were modest promotors of tubulin polymerisation, but less effective than paclitaxel. Analogues <bold>39</bold>, <bold>64</bold>, and <bold>65</bold> showed reduced microtubule formation consistent with tubulin inhibition. The variation in ring methoxy substituent with <bold>50</bold>, <bold>64</bold> and <bold>65</bold>, from o- to m- to p-, results in a concomitant reduction in cytotoxicity and a reduction in tubulin polymerisation, with p-OCH3<bold>50</bold> being the least active in this series of analogues. This presents <bold>64</bold> as a tubulin polymerisation inhibitor possessing novel chemotype and sub micromolar cytotoxicity. Naphthyl <bold>39</bold>, with complete inhibition of tubulin polymerisation, gave rise to a sub 0.2 mu M cell line cytotoxicity. Compounds <bold>39</bold> and <bold>64</bold> induced G(2) + M cell cycle arrest indicative of inhibition of tubulin polymerisation, with <bold>39</bold> inducing an equivalent effect on cell cycle arrest as nocodazole (<bold>68</bold>).<br />