Biologically active derivatives of gossypol: synthesis and antimalarial activities of peri-acylated gossylic nitriles

Abstract

A series of peri-acylated gossylic nitriles were synthesized from gossypol dioxime by treatment of the dioxime with the appropriate acid anhydride and its salt. The reaction pathway was elucidated by isolation and characterization of intermediates. Peri-acylated gossylic nitriles (acyl = acetyl, propionyl, butyryl, and valeryl) were compared with gossypol for activity against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. The gossylic nitriles all retain activity, with activity increasing with the length of the peri-acyl group. Gossylic nitrile 1,1'-divalerate shows antimalarial activity comparable to gossypol itself. The peri-acylated gossylic nitriles are strong inhibitors of parasite lactate dehydrogenase.

Identification of natural products and their derivatives as promising inhibitors of protein glycation with non-toxic nature against mouse fibroblast 3T3 cells

“…A large number of gossypol derivatives, such as Schiff's bases, esters, and ethers have been prepared. Several gossypol derivatives and analogs, such as compounds 3-6, possess activities such as antimalarial, anti-cancer, HIV (human immunodeficiency virus), and antiparasitic properties [31][32][33][34][35][36][37]. High throughput screening studies on a gossypol derivative 5 were performed in vivo and in vitro.…”

Isolation, cloning and sequence analysis of lactate dehydrogenase gene from Theileria annulata may lead to design of new antitheilerial drugs

“…Therefore, inhibition of a crucial enzyme, like LDH, in the glycolytic pathway is a rational approach for the development of a novel antitheilerial drug that will have a different mode of action than the existing drugs. Determination of differences between plasmodial LDH and host LDH indicated that both enzymes are distinguishable in their structural and kinetic properties (VanderJagt et al 1981;Royer et al 1986;Makler and Hinrichs, 1993;Dunn et al 1996;Turgut-Balik et al 2001a). Insertion of five amino acids between residues S 108 -R 109 in the substrate specificity loop (101-109) is characteristic for the apicomplexan parasite LDHs cloned to date.…”

“…Gossypol is a polyphenolic binaphthyl disesquiterpene compound present in cottonseed oil. Its derivatives have been tested against PfLDH and reported to be strong inhibitors of the parasite enzyme (Royer et al 1986). However, the cytotoxicity of gossypol has stopped any further development with regard to PfLDH inhibition (Granchi et al 2010).…”

Synthesis and Anti-Tumor Activities of Fluoride-Containing Gossypol Derivatives Compounds

“…Up to now, gossypol has been showed to exhibit anti-tumor activities towards a wide range of tumors, such as Ehrlich ascites tumor cells [2], SW-13 adrenocortical carcinoma cells [3], hormone-dependent and hormone-independent breast carcinoma [4,5], colon carcinoma cell line HT-29 and LoVo [6], human pancreatic cancer cell line [7], prostate cancer cell lines [8], head and neck cancer cells [9,10]. In addition, many synthesized gossypol derivatives and analogues possess disease-inhibiting activities [11], as anti-parasitic [12,13], anti-malarial [14][15][16], anti-HIV [17][18][19] and anticancer [20][21][22][23]. Derivatives such as gossypol Schiff bases prepared by modifying gossypol's aldehyde groups were supposed to Open Access Natural Science reduce its host toxicity ( Figure 1) while retaining or enhancing its therapeutic effects [24].…”