Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity.

Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.

Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic ß-cells protective agents for the treatment of type 2 diabetes mellitus.

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic ß-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic ß-cells protective activities and five derivatives were found to exhibit 20-50-fold higher activities than vincamine. Especially for compounds Vin-C01 and Vin-F03, exhibited a remarkable EC50 value of 0.22 µM and 0.27 µM, respectively. Their pancreatic ß-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-C01 and Vin-F03 could effectively promote ß-cell survival and protect ß-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent ß-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic ß-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.

Stereoselective synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine: observation of a substrate dependent diastereoselectivity reversal of an aldol reaction.

Starting from (-)-acetoxyglutarimide, the enantioselective multistep synthesis of (-)-desethyleburnamonine, (-)-vindeburnol and (-)-3-epitacamonine has been demonstrated via a common hydroxyl-lactam intermediate with very good overall yields. The acetoxy function from (-)-acetoxyglutarimide was initially used as a handle to induce enantioselectivity and then as a latent source of the ketone carbonyl group. Most importantly, substrate dependent reversal of the diastereoselectivity in ester aldol reactions of hexahydroindolo[2,3-a]quinolizinones has been reported.

Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines.

The asymmetric synthesis of N-allylic indoles is important for natural product synthesis and pharmaceutical research. The regio- and enantioselective N-allylation of indoles is a true challenge due to the favourable C3-allylation. We develop here a new strategy to the asymmetric synthesis of N-allylic indoles via rhodium-catalysed N-selective coupling of aryl hydrazines with allenes followed by Fischer indolization. The exclusive N-selectivities and good to excellent enantioselectivities are achieved applying a rhodium(I)/DTBM-Segphos or rhodium(I)/DTBM-Binap catalyst. This method permits the practical synthesis of valuable chiral N-allylated indoles, and avoids the N- or C-selectivity issue.

Synthesis of (+/-)-3H-epivincamine via a Rh(II)-triggered cyclization/cycloaddition cascade.

A synthesis of (+/-)-3H-epivincamine is reported. Important steps include (1) a Rh(II)-catalyzed intramolecular [3+2]-cycloaddition of an alpha-diazo indolo amide, (2) a reductive ring opening of the cycloadduct, (3) a decarboethoxylation reaction, and (4) a base-induced keto-amide ring contraction.

Syntheses of vinca alkaloids and related compounds. 104. A concise synthesis of (-)-vincapusine.

beta-Iodo-enamines with an eburnane skeleton (5a and 5c) were obtained with the aid of iodine from compounds 2a and 2c and were then transformed into hydroxyl lactams (6a and 6c) with CuSO4.5H2O in a mixture of DMF and water. Lactams (6a and 6c) were reduced selectively with BH3.SMe2 to result in the first synthesis of (-)-vincapusine (4a) as well as its natural 14-decarbomethoxy analogue (4c).

Synthesis of vinca alkaloids and related compounds. Part 84. Sulfonamide derivatives of some vinca alkaloids with cardiovascular activity.

(+)-Vincamine (1) and (+)-vinpocetine (2) were chlorosulfonylated and the resulting sulfonyl chloride isomers (3-6) were transformed into sulfonamides (7-10). The ester group of sulfonamides was modified by selective hydrolysis and transesterification. Apovincaminol derivatives (14-16) were also prepared by reduction. In addition to the known cerebrovascular effects of the unsubstituted compounds (1,2) sulfonamides also show a significant peripheral vasodilator effect.