Design, Synthesis and Biological Evaluation of Steroidal Glycoconjugates as Potential Antiproliferative Agents

Abstract

To systematically evaluate the impact of neoglycosylation upon the anticancer activities and selectivity of steroids, four series of neoglycosides of diosgenin, pregnenolone, dehydroepiandrosterone and estrone were designed and synthesized according to the neoglycosylation approach. The structures of all the products were elucidated by NMR analysis, and the stereochemistry of C20‐MeON‐pregnenolone was confirmed by crystal X‐ray diffraction. The compounds′ cytotoxicity on five human cancer cell lines was evaluated using a Cell Counting Kit‐8 assay, and structure–activity relationships (SAR) are discussed. 2‐deoxy‐d‐glucoside 5 k displayed the most potent antiproliferative activities against HepG2 cells with an IC50 value of 1.5 μM. Further pharmacological experiments on compound 5 k on HepG2 cells revealed that it could cause morphological changes and cell‐cycle arrest at the G0/G1 phase and then induced the apoptosis, which might be associated with the enhanced expression of high‐mobility group Box 1 (HMGB1). Taken together, these findings prove that the neoglycosylation of steroids could be a promising strategy for the discovery of potential antiproliferative agents.

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…The synthesis started with the epimerization of the angular methyl group on C-13. Only if the methyl group is in the α-position it should give the correct 41 when treated with m-CPBA. Next, the epoxy ring was opened accordingly in the presence of phosphoric acid and got the rearranged products (194,196), respectively (Scheme 27).…”

“…All of the MeONneoglycosides of DHEA 251a−n showed no effects against the five cancer cell lines at the concentration of 50 μM as compared to the other MeON-neoglycosides of diosgenin 252a−n, pregnenolone 253a−n/254a−n, and estrone 255a−n which are reported in the literature (Figure 11) (Table 28). 41 2.27. ENT-A013 (Novel Nerve Growth Factor Mimetic) Dehydroepiandrosterone Derivatives.…”

“… a Compounds 251a – n and 254a – n had IC 50 > 50 μM against the tested cells (data not shown). b Each value was determined in triplicate. The cells were continuously treated with compounds for 72 h. c Positive control …”

“…Figure 11. MeON-neoglycosides of diosgenin (252a−n), pregnenolone (253a-n/254a-n), and estrone (255a−n) 41. …”

“…b Each value was determined in triplicate. The cells were continuously treated with compounds for 72 h. c Positive control 41.…”