Semisynthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins.
The synthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins are reported. A general synthetic protocol, based on "C-5 camptothecin (C-5-CPT) enolate chemistry", allows one to obtain various C5-substituted analogues. All new compounds, obtained as 1:1 epimeric mixtures, were tested for their antiproliferative activity. Experimental data showed that all novel derivatives are less active than the reference compounds and that one of the two epimers is more active than the other. Molecular docking simulations were performed to achieve more insight into the interactions between the new C5-modified CPTs and Topo I. A good correlation was observed when the data of cytotoxicity and the values calculated for the free binding energy were combined.
Samorì
Cristian
C
Istituto CNR per la Sintesi Organica e Fotoreattività I.S.O.F., Area della Ricerca di Bologna, Via P. Gobetti 101, 40129 Bologna, Italy.
Guerrini
Andrea
A
Varchi
Greta
G
Fontana
Gabriele
G
Bombardelli
Ezio
E
Tinelli
Stella
S
Beretta
Giovanni Luca
GL
Basili
Serena
S
Moro
Stefano
S
Zunino
Franco
F
Battaglia
Arturo
A
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013816:Thermodynamics
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin