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Structure–Activity Relationship Study of 16 a‐Thiocamptothecins: an Integrated In Vitro and In Silico Approach
Author(s) -
Samorì Cristian,
Beretta Giovanni L.,
Varchi Greta,
Guerrini Andrea,
Di%emsp;Micco Simone,
Basili Serena,
Bifulco Giuseppe,
Riccio Raffaele,
Moro Stefano,
Bombardelli Ezio,
Zunino Franco,
Fontana Gabriele
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000369
Subject(s) - topoisomerase , chemistry , stereochemistry , in silico , moiety , ring (chemistry) , in vitro , hydrogen bond , molecular model , thio , dna , combinatorial chemistry , biochemistry , molecule , organic chemistry , gene
The instability of the hydroxylactone E ring represents a critical drawback of camptothecins, because the lactone ring is recognized to be essential for stabilization of topoisomerase I‐mediated DNA cleavage. In an attempt to investigate the effect of the thiopyridone pharmacophofore on the molecular and pharmacological features of the drug, we prepared a series of novel 16 a‐thiocamptothecin analogues. Due to the sulfur atom, a destabilization of the hydrogen bond between the hydroxy group in position 17 of the opened E ring and the carbonyl of the pyridone moiety is predicted, thus shifting the equilibrium toward the closed lactone form and increasing the lipophilic properties of the compounds. This feature was associated with superior antiproliferative potency, with reduced interaction with the human serum albumin and with substantial increase of the persistence of the topoisomerase I–DNA cleavable complex. These effects were prominent for thio‐SN38, the most active compound of the series. The favorable interactions at the molecular and cellular level of the reported thiocamptothecins confer promising features, and these compounds warrant preclinical development.