Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with N-phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, resulting in diphenylamine-type compounds. In silico studies of the Smiles rearrangement were performed. We also present the in vitro antiproliferative activity of the synthesized compounds against 60 human tumor cell lines (NCI60). The most potent derivative exhibited nanomolar antitumor activity on the MCF7 cell line of breast cancer (GI50 = 30 nM) and on the HCT-15 cell line of colon cancer (GI50 = 60 nM).

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.

The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 5′-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5′′-yl)quercetin, 6-(2′′-pyrrolidinon-5′′-yl)-(−)- and 8-(2′′-pyrrolidinon-5′′-yl)-(−)-epicatechin were prepared by acid-catalyzed regioselective Mannich reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.

The Diels-Alder reaction of vindoline and methyl vinyl ketone resulted in a Friedel-Crafts reaction product. In the reaction between the ortho-quinone derivative of vindoline and N-phenylmaleimide, two anomalous products were obtained, a vindoline dimer, and a condensed vindoline derivative.