Dynole-Based Dynamin Inhibitors as Novel Cytotoxic Agents

Abstract

Dynamin plays a crucial role in mitosis, and dynamin inhibition broadly correlates with cytotoxicity. Dynole 34–2, dynamin inhibitor, is highly cytotoxic, but its poor drug-like properties limit its in vivo development. Three focused libraries of dynole-based dynamin inhibitors were synthesized enhance their druglike properties while maintaining their dynamin inhibition and cytotoxicity. Iterative modifications were undertaken to probe the effects of changes to the cyanoacrylamide linker amide, alkyl chain moieties, the N-propyl-N,N-dimethylamino moiety and the indole core. These compounds were screened against: HT29 and SW480 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines to reveal a good correlation between dynamin inhibition and cytotoxicity. High potency against brain cancer cell lines was observed. The most dynamin active compounds returned average GI₅₀ values of 2.26 and 1.5 µM across the cell lines examined. The most active compound against 4 brain cancer cell lines averaged a GI₅₀ value of 4.7 µM; 10-fold improved over the gold standard for glioblastoma treatment; temozolomide. Importantly, this maintained a tPSA of 24.8Ų and cLogP of 4.11; appropriate for blood brain barrier penetration. This active analogue in this series was (Z)-2-(3,4-dichlorophenyl)-3-(1-(3-(dimethylamino)propyl)-1H-pyrrol-3-yl)acrylonitrile (34).