Asparagusic Acid – A Unique Approach toward Effective Cellular Uptake of Therapeutics: Application, Biological Targets, and Chemical Properties

Abstract

The synthetic approaches towards unique asparagusic acid and its analogues as well as its chemical use, the breadth of its biological properties and their relevant applications have been explored. The significance of the 1,2‐dithiolane ring tension in dithiol‐mediated uptake and its use for the intracellular transport of molecular cargoes is discussed alongside some of the challenges that arise from the fast thiolate‐disulfide interchange. The short overview with the indication of the available literature on natural 1,2‐dithiolanes synthesis and biological activities is also included. The general review structure is based on the time‐line perspective of the application of asparagusic acid moiety as well as its primitive derivatives (4‐amino‐1,2‐dithiolane‐4‐carboxylic acid and 4‐methyl‐1,2‐dithiolane‐4‐carboxilic acid) used in clinics/cosmetics, focusing on the recent research in this area and including international patents applications.

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake

“…The bioinspired ETPs exchange ultrafast because ring tension is maximal, but are poorly retained on thiol/ate affinity columns . In CAXs derived from asparagusic acid (AspA), reduced ring tension compared to ETP coincides with reduced cell penetration, while less strained disulfides show even weaker activity. , …”

“…The bioinspired ETPs exchange ultrafast because ring tension is maximal, but are poorly retained on thiol/ate affinity columns. 51 In CAXs derived from asparagusic acid (AspA), 55 reduced ring tension compared to ETP coincides with reduced cell penetration, while less strained disulfides show even weaker activity. 51,52 Cyclic thiosulfonates (CTOs) operate on a higher oxidation level, which accelerates the first and adds selectivity to the second step of cascade exchange, promising also against the entry of SARS-CoV-2 lentivectors.…”

Design, Synthesis, and Bioactivity Evaluations of 3‐Methylenechroman‐2‐one Derivatives as Thioredoxin Reductase (TrxR) Inhibitors

“…As part of our ongoing efforts to discover small, natural‐like therapeutic molecules that regulate cellular redox system, here we report 3‐methylenechroman‐2‐ones as novel TrxR1 inhibitors. In our previous study, we synthesized a series of 3,4‐unsubstituted coumarins and found that the substitution at C‐6 of coumarin core exhibits stronger inhibitory effects against TrxR1 than other analogues [7b,c] . Based on our observation, it was assumed that the activated double bond serves as a crucial pharmacophore during the interaction with TrxR.…”

May 1,2-Dithiolane-4-carboxylic Acid and Its Derivatives Serve as a Specific Thioredoxin Reductase 1 Inhibitor?

“…On the other hand, TrxR1 can also be targeted by compounds that mimic its natural substrates with disulfide moiety, where the participation of the second TrxR1 redox-active site, containing a homological sequence of Cys-Val-Asn-Val-Gly-Cys-, is not excluded [ 15 ]. The investigation of cyclic disulfide analogs, such as asparagusic acid [ 16 , 17 ] and its analogs [ 18 ], remains an attractive and less-investigated concept in the design of potential TrxR inhibitors.…”