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Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach.
ChemMedChem. 2010 Dec 03; 5(12):2006-15.C

Abstract

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.

Authors+Show Affiliations

Istituto CNR per la Sintesi Organica e Fotoreattività "I.S.O.F.", Bologna, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21069656

Citation

Samorì, Cristian, et al. "Structure-activity Relationship Study of 16 A-thiocamptothecins: an Integrated in Vitro and in Silico Approach." ChemMedChem, vol. 5, no. 12, 2010, pp. 2006-15.
Samorì C, Beretta GL, Varchi G, et al. Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach. ChemMedChem. 2010;5(12):2006-15.
Samorì, C., Beretta, G. L., Varchi, G., Guerrini, A., Di Micco, S., Basili, S., Bifulco, G., Riccio, R., Moro, S., Bombardelli, E., Zunino, F., & Fontana, G. (2010). Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach. ChemMedChem, 5(12), 2006-15. https://doi.org/10.1002/cmdc.201000369
Samorì C, et al. Structure-activity Relationship Study of 16 A-thiocamptothecins: an Integrated in Vitro and in Silico Approach. ChemMedChem. 2010 Dec 3;5(12):2006-15. PubMed PMID: 21069656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-activity relationship study of 16 a-thiocamptothecins: an integrated in vitro and in silico approach. AU - Samorì,Cristian, AU - Beretta,Giovanni L, AU - Varchi,Greta, AU - Guerrini,Andrea, AU - Di Micco,Simone, AU - Basili,Serena, AU - Bifulco,Giuseppe, AU - Riccio,Raffaele, AU - Moro,Stefano, AU - Bombardelli,Ezio, AU - Zunino,Franco, AU - Fontana,Gabriele, PY - 2010/11/12/entrez PY - 2010/11/12/pubmed PY - 2011/3/22/medline SP - 2006 EP - 15 JF - ChemMedChem JO - ChemMedChem VL - 5 IS - 12 N2 - 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. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/21069656/Structure_activity_relationship_study_of_16_a_thiocamptothecins:_an_integrated_in_vitro_and_in_silico_approach_ L2 - https://doi.org/10.1002/cmdc.201000369 DB - PRIME DP - Unbound Medicine ER -