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Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects. Besides this, the conjugate could exhibit increased efficiency against resistant cells, e.g., due to the altered internalization pathway. Oligoarginines, as cell-penetrating peptides, can transport covalently attached compounds into different kinds of cells and enhance the efficiency of those compounds. We report here the coupling of vinblastine through its carboxyl group at position 16 with the N-terminal amino function of L-Trp methyl ester. After hydrolysis of the ester group, 17-desacetylvinblastineTrp was conjugated to the N-terminal amino group of oligoarginine via the C-terminal carboxyl group of the Trp moiety in solution. The antitumor effect of conjugates was studied on sensitive and resistant human leukemia (HL-60) cells in vitro. Our data suggest that all conjugates investigated possess an antiproliferative effect against the studied cells. However, the effect was dependent on the number of Arg residues in the conjugates: Arg₈ > Arg₆ ≫ Arg₄. The conjugate with Arg₈ exhibited similar efficicacy as compared with free 17-desacetylvinblastineTrp. The in vitro studies also showed that the tubulin binding ability of vinblastine was essentially preserved even in the octaarginine conjugate. We also observed that two isomers were formed during conjugation. These isomers showed different levels of activity against tubulin polymerization in vitro and in vivo. The 17-desacetylvinblastineTrp-Arg₈-1 isomer conjugate possessed high selectivity against the mitotic spindles. HRMS and NMR data suggest that 17-desacetylvinblastineTrp-Arg₈-1 and 17-desacetylvinblastineTrp-Arg₈-2 are epimers at the tryptophan α carbon atom.

The first syntheses of the alkaloids (−)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-Na-methylvoaphylline/hecubine (5), and (−)-lochnericine (2) were achieved by stereoselective epoxidation starting from (−)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.

Using our previously reported convergent synthetic strategy, secondary amine, methyl 2-[3-(2-[benzylamino]ethyl)indol-2-yl]-3-hydroxypropionate (6), and aldehyde, ethyl 2-ethyl-4-formylbutanoate (9), reacted to give tetracyclic esters ,pyrrolo[2,3-d]carbazole derivatives 10 and 11, which readily led to pentacyclic lactams indolizino[8,1-cd]carbazole derivatives 14-16. Selective reduction of these products gave (±)-pseudovincadifformine (4), (±)-20-epipseudovincadifformine (5), and (±)-14-epipseudovincadifformine (20). 2-ethyl-4-formylbutyl benzoate 23 was also prepared and could be directly used for synthesizing (±)-20-epipseudovincadifformine (5). The introduction of the double bond into ring D of the pseudoaspidospermane skeleton was successfully achieved to obtain 21-oxopseudotabersonine (30)

Compound 3, which has an indole skeleton containing a masked acryl ester function, was synthesized from the hydrochloride of 2-(ethorycarbonyl)tryptamine (2). The cycloaddition of 3 with methyl 4-formylhexanoate (21) or with 5-(benzoylocy)-2-ethylpentanal (33) yielded the starting materials for beget compounds (±)-vincadifformine (4), (±)-3-oxotabersonine (42), and (±)-tabersonine (43). The synthesis of vincadifformine (4) was achieved in two different ways: via 3-oxovincadifformine (7) and via tetracyclic benzoate esters 37 and 38. The double bond requiredin tabersonine (43) and 3-oxotabersonine (42) was introducedby treatment of 3-thioxovincadifformine (39) with p-toluenesulfinyl chloride