Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy.

A series of 7-methylenedehydrobenzo[7]annulen-5-ol hexacarbonyldicobalt complexes were generated by Hosomi–Sakurai reactions of allylsilanes containing o-alkynylarylaldehyde-Co2(CO)6 complexes. One of the cyclization products was converted into its corresponding dihydrobenzo[7]annulen-7-ol hexacarbonyldicobalt complex, an immediate precursor to a benzodehydrotropylium–Co2(CO)6. The cation was generated in situ and reacted with four nucleophiles, and its aromatic stabilization was determined by computational methods.

This paper is dedicated to Manfred Schlosser, in recognition of his many contributions to organic chemistry but with particular admiration for his work in remote functionalization by way of organometallic intermediates.BF 3 ⋅OEt 2 (cat.

Lewis Acid Catalyzed Synthesis of Allocolchicinoids. -A three-step access to (biphenyl-2-yl)prop-2-en-1-ones is described which serve as substrates for the cyclization to allocolchicinoids. Further transformation of the cyclization products via enantioselective reduction of their keto functionality and functionalization of the thus obtained hydroxy functionality is exemplified. An unexpected cyclization involving a rearrangement is also investigated. -(MEHDI, M. A.; DJURDJEVIC, S.; GREEN*, J. R.; Synlett 26 (2015) 17, 2408-2412, http://dx.