Antitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents.
Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4'-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7568, USA.
Deyong
D
Ye
Qian
Q
Shi
Chung-Hang
CH
Leung
Seung-Whan
SW
Kim
Shin-Young
SY
Park
Elizabeth A
EA
Gullen
Zao Li
ZL
Jiang
Hao
H
Zhu
Susan L
SL
Morris-Natschke
Yung-Chi
YC
Cheng
Kuo-Hsiung
KH
Lee
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002166:Camptothecin / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D011034:Podophyllotoxin / Q000737:chemistry*; D013237:Stereoisomerism; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D011034:Podophyllotoxin; D002166:Camptothecin