Triorganotin complexes in cancer chemotherapy: Mechanistic insights and future perspectives

Abstract

Current anticancer drug discovery and development efforts are aimed at identifying new complexes that can potently and selectively target DNA and modulate the functions of target proteins. Tin complexes, categorized as monoorganotin (RSnL3), diorganotin (R2SnL2), triorganotin (R3SnL), or tetraorganotin (R4SnL), are one of the most studied complexes in the metal‐based anticancer drug discovery and development field. Among these, diorganotins and triorganotins are widely reported to possess promising anticancer properties, with triorganotins offering several potential advantages over diorganotins, such as a higher total surface area causing higher lipophilicity and hence higher cytotoxicity in cancer cells. However, information on triorganotins' direct therapeutic targets, an in‐depth understanding of their mechanism of action, and useful therapeutic strategies are still lacking. In this review, we discuss the results from in vitro and in vivo mechanistic studies of triorganotin complexes as reported in recent years (2007–2019) and elaborate on the underlying mechanisms that could aid in the identification of triorganotin complex molecular targets. We conclude by identifying present obstacles faced by triorganotin complexes that avert their translation to the clinical phase and current strategies employed to overcome the aforementioned obstacles, and we offer considerations for their future development. These findings are anticipated to stimulate further developments of novel and innovative triorganotin complexes as anticancer drug candidates.

Syntheses, structures, and the in vitro anticancer mechanism of triorganotin (IV) complexes based on 4,4′‐stilbenedicarboxylic acid

“…Organotin (IV) complexes, a class of organometallic compounds, have drawn considerable interest due to their diverse structures and extensive applications in chemistry, [10] materials, [11] and biology. [12] Early in the 80s, Marcel Gielen studied organotin compounds and discovered the bioactivity of organotin (IV) compounds. [13,14] Since then, a variety of diorganotin and triorganotin (IV) complexes were successfully synthesized and structurally characterized, and various structures have been shown, including drum-shaped, trapezoidal, cage-shaped, cyclic trimers, and so forth.…”

“…[24] Although the structure-activity relationship of organotin (IV) complexes of many oxygen-donating ligands has been investigated, information on the mechanisms of anticancer activity for the organotin (IV) complexes is relatively inadequate. [12,25] In view of the above considerations, designing and synthesizing new organotin (IV) carboxylates to study their anticancer properties and mechanisms have a significant meaning.…”

C,O‐Chelated organotin(IV) derivatives as potential anticancer agents: Synthesis, characterization, and cytotoxic activity

“…Trialkyltin(IV) compounds are the most toxic among of all R n SnL 4‐n species, yet the toxicity of triaryltin(IV) derivatives decreases if the aryl functions are bulkier. [ 13 ] Triorganotin(IV) carboxylates, halides, and other related derivatives have been intensively studied recently for their in vitro [ 14–19 ] and in vivo [ 20–23 ] antitumor activity emphasizing again that the biological activity of these organotin(IV) molecules is highly influenced by the organic groups bounded to the metal center as Gielen mentioned earlier. [ 6 ] Besides, triorganotin(IV) derivatives exhibit a better lipophilicity than diorganotin species, owed to an increased total surface area, which makes them more capable to penetrate the cell membrane.…”

“…Considering these aspects, many triorganotin(IV) derivatives with various oxygen‐donor ligands, that is, carboxylic acids (e.g., 4‐methoxyphenylacetic, [ 27 ] trifluoroacetic, [ 28 ] 3,5‐di‐ tert ‐butyl‐4‐hydroxybenzoic, [ 29 ] and nicotinic and isonicotinic acid [ 30,31 ] ), amino‐acids (e.g., 3‐aminobenzoic, [ 32 ] 4‐aminobenzoic, [ 32 ] or 5‐amino‐2‐chlorobenzoic [ 33,34 ] ), or nonsteroidal anti‐inflammatory drugs (NSAIDs) (e.g., indomethacin [ 35 ] and ibuprofen [ 36 ] ) displayed higher cytotoxicity with lower IC 50 values than cisplatin or other standard treatments. [ 19 ]…”

Synthesis, characterisation and biological activity of diorganotin compounds of (E)-N'-(5-nitro-2-hydroxybenzylidene)-3-hydroxy-2-naphthohydrazide

“…Organotin compounds have been widely studied owing to their well-documented versatile chemistry and their potential as biologically active compounds [1][2][3][4][5][6][7][8][9]. An important class of organotin compounds are those derived from Schiff bases.…”