Aromatic Electrophilic Substitutions on Vindoline

Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI 50 values on most of the cell lines.

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Synthesis of Novel Vindoline‐Chrysin Hybrids

Mayer

Nagy

Keglevich

et al. 2021

Chemistry & Biodiversity

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Aromatic Electrophilic Substitutions on Vindoline.

et al. 2007

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Alkaloids U 0600Aromatic Electrophilic Substitutions on Vindoline. -Nitration of 10-bromo derivative (V) leads to the unexpected, anomalous 12-bromo-10-nitrovindoline (VI) and appears to be a further example of the rearrangement discovered by Reverdin. Nitration of the 10-chloro analogue (VII) leads to the expected derivative (VIII). -(GORKA-KERESKENYI, A.; SZABO, L.; HAZAI, L.; LENGYEL, M.; SZANTAY, C. J.; SANTA, Z.; KALAUS, G.; SZANTAY*, C.; Heterocycles 71 (2007) 7, 1553-1563; Dep. Org. Chem. Technol., Budapest Univ. Technol. Econ., H-1521 Budapest, Hung.; Eng.) -K. Woydowski 44-184

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The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell‐penetrating peptide

Bánóczi

Keglevich

Szabó

et al. 2018

Journal of Peptide Science

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Some Vinca alkaloids (eg, vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G. Don, itself, has no antitumor activity. In our novel research program, we have prepared and identified new vindoline derivatives with moderate cytostatic activity. Here, we describe the effect of conjugation of vindoline derivative with oligoarginine (tetra-, hexa-, or octapeptides) cell-penetrating peptides on the cytostatic activity in vitro and in vivo. Br-Vindoline-(l)-Trp-OH attached to the N-terminus of octaarginine was the most effective compound in vitro on HL-60 cell line. Analysis of the in vitro activity of two isomer conjugates (Br-vindoline-(l)-Trp-Arg and Br-vindoline-(d)-Trp-Arg suggests the covalent attachment of the vindoline derivatives to octaarginine increased the antitumor activity significantly against P388 and C26 tumour cells in vitro. The cytostatic effect was dependent on the presence and configuration of Trp in the conjugate as well as on the cell line studied. The configuration of Trp notably influenced the activity on C26 and P388 cells: conjugate with (l)-Trp was more active than conjugate with the (d)-isomer. In contrast, conjugates had very similar effect on both the HL-60 and MDA-MB-231 cells. In preliminary experiments, conjugate Br-vindoline-(l)-Trp-Arg exhibited some inhibitory effect on the tumor growth in P388 mouse leukemia tumor-bearing mice. Our results indicate that the conjugation of modified vindoline could result in an effective compound even with in vivo antitumor activity.

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Aromatic Electrophilic Substitutions on Vindoline

Cited by 11 publications

References 11 publications

Synthesis of Novel Vindoline‐Chrysin Hybrids

Synthesis of Novel Vindoline‐Chrysin Hybrids

Aromatic Electrophilic Substitutions on Vindoline.

The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell‐penetrating peptide

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