Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H2S).

L-Cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (H2S) in aqueous and cellular media. Considering the cytoprotective roles of H2S, the present adjuvant strategy would be helpful in minimizing the anti-cancer drug-induced side-effects.

Thioredoxin reductase-triggered fluorogenic donor of hydrogen sulfide: a model study with a symmetrical organopolysulfide probe with turn-on near-infrared fluorescent emission.

We describe herein the rational development of an organopolysulfide-based fluorogenic donor of hydrogen sulfide (H2S) DCI-PS, which can be activated by the antioxidant selenoenzyme thioredoxin reductase (TrxR) with concomitant release of the dicyanoisophorone-based near-infrared (NIR) fluorophore. Along with the polysulfide probe DCI-PS capable of releasing the NIR fluorophore and H2S, the corresponding disulfide-probe DCI-DS was also rationally designed and synthesized, which releases the fluorophore without donating H2S. Detailed spectroscopic and kinetic studies in an aqueous medium revealed significantly higher reactivity of the probes towards DTT (for TrxR activity) over the well-known cellular abundant biothiol GSH. Mechanistically, the nucleophilic attack at the disulfide/polysulfide linkage by the thiol/selenol group of the bio-analytes leads to the self-immolative cyclization process with the release of the turn-on fluorophore with/without H2S. Considering the overexpression of mammalian TrxR in cancer cells, the turn-on fluorogenic H2S donation process from the cellular non-toxic DCI-PS was validated in a representative breast cancer cell line (MDA-MB-231) for the sustained donation of H2S with concomitant release of the red-emitting NIR fluorophore. The TrxR-triggered fluorescence turn-on process in DCI-PS was further supported by the significant inhibition of the fluorogenic process in the presence of TrxR-selective small-molecule inhibitors and by the significant binding affinity predicted by the protein-ligand docking study. Results with the antioxidant enzyme-triggered intracellular sustained donation of H2S with concomitant fluorescence turn-on will certainly find wider biomedical applications in the near future, particularly in H2S-mediated therapeutics in disease states.

Benzimidazole- and Imidazole-Fused Selenazolium and Selenazinium Selenocyanates: Ionic Organoselenium Compounds with Efficient Peroxide Scavenging Activities.

Three new classes of ionic organoselenium compounds containing cationic benzimidazolium and imidazolium ring systems with selenocyanates as counterions are described. The cyclization of N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)2-Br and N-(CH2)3-Br groups in the presence of potassium selenocyanate (KSeCN) led to formation of the corresponding selenazolium selenocyanates (21a, 21b, 22a, and 22b) and selenazinium selenocyanates (21c, 21d, 22c, and 22d). However, the open-chain selenocyanates with additional selenocyanate counterions (21e, 21f, 22e, and 22f) were formed from the N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)6-Br groups. Mechanistic studies were carried out to understand the feasibility of such cyclization processes in the presence of KSeCN. The compounds were studied further for their potencies to catalytically reduce H2O2 in the presence of thiols. Interestingly, the cyclic selenazolium (21a, 21b, 22a, and 22b) and selenazinium compounds (21c, 21d, 22c, and 22d) exhibited significantly higher antioxidant activities than the corresponding acyclic selenocyanates (21f, 22e, and 22f). Selected compounds (22d and 22e) were further evaluated for their potencies in modulating the intracellular level of reactive oxygen species (ROS) in a representative macrophage cell line (RAW 264.7). Owing to the cationic nature of compounds, they may target and scavenge mitochondrial ROS in the cellular medium.

The biothiol-triggered organotrisulfide-based self-immolative fluorogenic donors of hydrogen sulfide enable lysosomal trafficking.

Biothiol-reactive organotrisulfide-based self-immolative fluorogenic donors of H2S are rationally designed for the efficient monitoring of intracellular and lysosomal trafficking of H2S with a concomitant turn-on fluorescence. The non-toxic nature of the donors with a sustained release of H2S will certainly be helpful for their biomedical applications in the future.

Trisulfides over disulfides: highly selective synthetic strategies, anti-proliferative activities and sustained H2S release profiles.

Temperature- and solvent-induced selective synthesis of trisulfides and disulfides is demonstrated. A remarkable selectivity was achieved using Na2S as a sulfur-transfer agent under mild, greener, catalyst-free and additive-free conditions. This study reveals trisulfides as a better model than disulfides in general for a sustained release of H2S and potent anti-cancer activities.