Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids

Abstract

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.

Flavone Hybrids and Derivatives as Bioactive Agents

“…Hybrid 11 was obtained in this case also via a click reaction. Some of the compounds (11) showed moderate antiproliferative activity on cell line MCF-7 of breast cancer (IC50 = 14.5-19.1 µM), and hybrid 9 (R=CH3, R 1 =H) showed moderate antimycobacterial activity against a bovis strain. The triazole ring is connected to the flavone via an amino group in the following hybrids (Figure 6).…”

“…Important groups of natural compounds are the flavone alkaloids and Vinca alkaloids [11]. Flavone hybrids of vindoline (Figure 14) coupled in position 10 of vindoline (34,35) were synthesized with short or longer linkers.…”

“…There are several reviews in the literature about flavone hybrids, which primarily present a specific field of biological activity, e.g., anticancer agents [9] or esterase inhibitors [10]. On the other hand, further reviews summarize flavone hybrids formed with specific coupling components, such as 2-pyrrolidones (flavone alkaloids) and arylamines [11], with Vinca alkaloids [12] as well as 1,2,3-triazole pharmacophores [13].…”

Graphene and Graphene Based Nanocomposites for Bio‐Medical and Bio‐safety Applications

“…Authors observed the properties of GO and bacterially rGO on cellular survival and in human breast cancer cell. 14,15‐cyclopropanovinorelbine (Scheme 8) has important conclusion in the case of non‐small cell lung cancer, colon cancer, central nervous system cancers, melanoma and human breast cancer [102] . The most effective therapy for breast cancer, cancer in vitro and vivo is volatile organic compounds (VOCs).…”

“…14,15-cyclopropanovinorelbine (Scheme 8) has important conclusion in the case of non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma and human breast cancer. [102] The most effective therapy for breast cancer, cancer in vitro and vivo is volatile organic compounds (VOCs). Ketones, alcohols, aldehydes, hydrocarbons, isocyanates, terpenes, sulphides, and amines are just a few of the many carbon-based compounds that make up VOCs.…”