Synthesis and Biological Evaluation of Pentacyclic Strychnos Alkaloids as Selective Modulators of the ABCC10 (MRP7) Efflux Pump

Abstract

The selective modulation of ABC efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represents a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), A (5), and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and evaluated compounds 1–3, 5 in biochemical assays with ABCC10 and P-gp. Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.5 μM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 μM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.

Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine

“…Finally, upon treatment of a deaerated NMP solution of 4 with DBU at 200 °C for 40 min, a mixture of the expected isostrychnine (13) and 13-epi-isostrychnine (16) was obtained in a 2:1 ratio in 61% yield (Scheme 8). It should be noted that the formation of 16 was also observed in the previous screening, but its characterization was not complete due to the difficulties with its purification (e.g., its high polarity and the presence of other polar byproducts).…”

“…As part of our research program aimed at developing and applying novel synthetic methods for efficiently accessing complex indole alkaloids over the past decade, [10][11][12][13][14][15][16][17][18][19][20] we recently communicated the first enantiospecific syntheses of bis-Strychnos alkaloids 1-3. 21 Herein, we provide a full account of our synthetic efforts, from failure to success, employed in the preparation of these unique natural products.…”

“…-)-(3aS,5R,5aS,5a1S,13bR,E)-14-(2-Hydroxyethylidene)-1,2,3a,4,5a,5a1-hexahydro-5H,8H-3,5-ethanopyrido [1,2,3-lm]pyrrolo[2,3-d]carbazol-8-one(16) …”

Total Syntheses of (–)-Alstolucines A, B, and F, (–)-Echitamidine, and (–)-N-Demethylalstogucine

“…Recourse to reductive amination ultimately proved successful (Scheme 4). 1,4 Ethyl glyoxalate and 9 were condensed in the presence of 4-Ǻ molecular sieves to form the imine, which was then reduced using lithium aluminum hydride to give amino alcohol 16. Finally, N-Boc protection of 16 using di-tert-butyl carbonate and Hünig's base afforded 17 in 57% yield over two steps.…”

“…The structural complexity of these targets, coupled with their novelty and biological significance, motivated us to prepare these in asymmetric fashion, which we recently communicated. 4 In 1994, Kuehne, reported the racemic syntheses of echitamidine (24) by the stereoselective hydride reduction of alstolucines B (3). Moreover, 3 was equilibrated to alstolucine F (4) in 2:1 ratio via treatment with sodium methoxide in methanol.…”