Inhibitors of tubulin polymerization: synthesis and biological evaluation of hybrids of vindoline, anhydrovinblastine and vinorelbine with thiocolchicine, podophyllotoxin and baccatin III.
A series of novel hybrid compounds obtained by the attachment of anhydrovinblastine, vinorelbine, and vindoline to thiocolchicine, podophyllotoxin, and baccatin III are described. Two types of diacyl spacers are introduced. The influence of the hybrid compounds on tubulin polymerization is reported. The results highlight the importance of the length of the spacer. Immunofluorescence microscopy and flow cytometry measurements that compound with the best in vitro activity could disrupt microtubule networks in cell and prevent the formation of the proper spindle apparatus, thereby causing cell cycle arrest in the G2/M phase. The newly synthesized compounds were tested in the human lung cancer cell line A549.
Passarella
Daniele
D
Dipartimento di Chimica Organica e Industriale, Via Venezian 21, Università degli Studi di Milano, 20133 Milano, Italy. Daniele.Passarella@unimi.it
Giardini
Alessandra
A
Peretto
Bruno
B
Fontana
Gabriele
G
Sacchetti
Alessandro
A
Silvani
Alessandra
A
Ronchi
Cristina
C
Cappelletti
Graziella
G
Cartelli
Daniele
D
Borlak
Jurgen
J
Danieli
Bruno
B
D000470:Alkaloids / Q000138:chemical synthesis* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000633:toxicity; D045744:Cell Line, Tumor; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D020650:Combinatorial Chemistry Techniques; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D011034:Podophyllotoxin / Q000138:chemical synthesis* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000633:toxicity; D013552:Swine; D043823:Taxoids / Q000138:chemical synthesis* / Q000633:toxicity; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000633:toxicity; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000633:toxicity; D000077235:Vinorelbine
D000470:Alkaloids; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; C073950:baccatin III; C014856:thiocholchicine; C009667:vindoline; D014747:Vinblastine; D011034:Podophyllotoxin; D000077235:Vinorelbine; D003078:Colchicine