Stereoselective Synthesis and Application of Gibberellic Acid-Derived Aminodiols

Abstract

A series of gibberellic acid-based aminodiols was designed and synthesized from commercially available gibberellic acid. Exposure of gibberellic acid to hydrochloric acid under reflux conditions resulted in aromatization followed by rearrangement to form allo-gibberic acid. The key intermediate, ethyl allo-gibberate, was prepared according to literature methods. Epoxidation of key intermediate and subsequent ring-opening of the corresponding epoxide with different nucleophiles resulted in N-substituted aminodiols. The regioselective ring closure of N-benzyl-substituted aminodiol with formaldehyde was also investigated. All aminodiol derivatives were well characterized using modern spectroscopic techniques and evaluated for their antiproliferative activity against a panel of human cancer cell lines. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems. The results indicated that aminodiols containing aromatic rings on their nitrogen substituents displayed significant cytotoxic effects. Among these agents, N-naphthylmethyl-substituted aminodiols were found to be the most potent candidates in this series. One of these molecules exhibited a modest cancer selectivity determined by non-cancerous fibroblast cells. A docking study was also made to exploit the observed results.

Stereoselective synthesis and antiproliferative activity of allo-gibberic acid-based 1,3-aminoalcohol regioisomers

“… 12 Compounds 3 and 4 were prepared as mentioned in our previous work. 22 All spectroscopic data were similar to those described therein.…”

“…12,16 As mentioned in our previous work, cis -epoxy alcohol 4 was prepared in a stereospecific manner by m -CPBA-mediated epoxidation of allo -gibberic acid ethyl ester 3 (Scheme 1). 22…”

“…12,16 As mentioned in our previous work, cis-epoxy alcohol 4 was prepared in a stereospecific manner by m-CPBA-mediated epoxidation of allo-gibberic acid ethyl ester 3 (Scheme 1). 22 The key intermediate hydroxymethyl ketone 5 was obtained by HCl-mediated rearrangement of epoxy alcohol 4. In this process, a six-membered transition state is formed and the carbonium ion is stabilised by Wagner-Meerwein rearrangement with the inversion of ring C/D configuration.…”

“…1 exhibited a modest cancer selectivity (IC 50 = 4.38–7.49 μM) over NIH/3 T3 fibroblast cells (IC 50 = 10.88 μM). 22 Furthermore, a group of allo -gibberic acid-based aminoalcohols B shown in Fig. 1 has been recently considered for their antimicrobial activity against a panel of multidrug-resistant Gram-negative bacteria.…”