Cysteine-modifying agents: a possible approach for effective anticancer and antiviral drugs.

Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones

“…Thus, selectivity of adduction is governed by both the recipient nucleophile and the chemistry of the adducting electrophile. Likewise, Cys-239 in tubulin is preferentially alkylated by anticancer drugs, including the colchicines, Vinca alkaloids, rhizoxin/maytansine, and taxanes (Jordan et al, 1998;Shan et al, 1999;Kavallaris et al, 2001;Casini et al, 2002;Scozzafava et al, 2002), and carbonic anhydrase III, which contains five cysteine residues, is selectively alkylated at Cys-186 by acrylonitrile (Nerland et al, 2003). Cysteine thiols are clearly common targets of reactive electrophilic metabolites and endogenous electrophiles, including lipid-derived ␣,␤-unsaturated aldehydes, such as 4-hydroxynonenal (4-HNE) and 4-oxononenal, and reactive oxygen species.…”

“…Such reactive metabolites usually have low electron density and react with molecular centers of high electron density (i.e., nucleophiles). Target proteins for adduction usually contain strong nucleophilic sites, including cysteine thiols, lysine amines, histidine imidazoles, and protein N-terminal amines, which are readily attacked by reactive species (Guengerich et al, 2001;Casini et al, 2002). Other proteins contain weaker nucleophilic sites, including methionine sulfur, arginine guanidinium, tyrosine phenols, serine and threonine hydroxyls, and aspartate and glutamate carboxyls.…”

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…The redox mechanism of action associated with experimental antiretrovirals including the 2,2 0 -dithiobisbenzamide-derivative DIBA (NSC 654077; Fig. 4-37) that inactivates HIV-1 by NCp7 zinc finger disruption has been elucidated in much detail (52,155). Initially, the antiviral agent forms an intermolecular disulfide bond via disulfide exchange through electrophilic attack on one of the sulfur atoms coordinating the Zn(II) ion of the zinc finger.…”

“…The selectivity of electrophilic agents toward zinc fingers depends on multiple physicochemical parameters including redox potential, reactive proximity, and noncovalent ligandbinding affinity (23,52,361). For example, electrochemical analysis of the Sp1 zinc finger by cyclic voltammetry revealed a redox potential that thermodynamically favors preferential oxidative disruption of this particular thiol target by redox cycler prototype organochalcogens in oxidatively stressed cells with lowered glutathione content (128).…”

New Aryl-1,3-thiazole-4-carbohydrazides, Their 1,3,4-Oxadiazole-2- thione, 1,2,4-Triazole, Isatin-3-ylidene and Carboxamide Derivatives. Synthesis and Anti-HIV Activity

“…Moreover, thiazoles serve as important pharmacodynamic nuclei, and their incorporation in different heterocyclic scaffolds results in varied biological activities such as antitumor [17], anticonvulsant [18], antimicrobial [19 -22], anti-inflammatory [23], antiprotozoal [24], and antityrosinase [25]. Furthermore, some amino acid derivatives such as the lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole [26], amino acid derivatives of paclitaxol [27], pyroglutamic acid [28], cysteine-modifying agents [29], and isoquinoline carboxylic acid derivatives [30] were reported as potential HIV protease inhibitors [31]. Recently, Al-Masoudi et al [32 -36] have reported the synthesis of various naphthalene, coumarin and sebacoyl derivatives bearc 2012 Verlag der Zeitschrift für Naturforschung, Tübingen · http://znaturforsch.com ing amino acid moieties as potential anti-HIV candidates.…”