Synthesis and in Vitro Antitumor Effect of Vinblastine Derivative−Oligoarginine Conjugates

Abstract

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.

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“…Vinblastine-16-hydrazide-17-OH was obtained by reaction with hydrazine monohydrate in methanol as described previously. 36 The corresponding hydrazide (0.075 g, 0.1 mmol, 1 eq.) was treated for 10 min with 1-[bis (dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.046 g, 0.12 mmol, 1.2 eq.…”

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“…The obtained conjugates exhibited significant antitumor effect against P388 and L1210 leukemia in mice. At the same time (D)-and (L)-tryptophan derivatives at the 16-position of desacetylvinblastine were conjugated through the carboxyl group with oligoarginine octapeptide as a carrier peptide at the N-terminus by Bánóczi et al [46] One of the obtained stereoisomers showed a selective cytotoxic effect against the HL-60 human leukemia cells of higher proliferation rate.…”

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“…All the derivatives retained the ability of binding to tubulin and also the antiproliferative activity, which was dependent on the number of arginines. In leukemic cells (HL-60 cell line), the greatest activity (IC 50 ≈ 1.6 µM) was exhibited by the derivative with octa-arginines while the lowest one by the derivative with the shortest oligopeptide (IC 50 ≈ 5 µM) [ 157 ].…”