Synthesis and antitumor activity of several new analogues of penclomedine and its metabolites.
Analogues of penclomedine (PEN, 3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine) and its metabolites have been synthesized and evaluated as potential antitumor agents. PEN and 4-DMPEN (3,5-dichloro-4-hydroxy-6-methoxy2-(trichloromethyl)pyridine (3a)), the major plasma metabolite in patients, were modified at 4- and 6-positions with different alkyl, aryl, and ester groups. All of the analogues and many of the intermediates were evaluated against the PEN-sensitive MX-1 human breast tumor xenograft in vivo, and several analogues of PEN and 4-DMPEN showed modest to curative activity.
Tiwari
Anita
A
Drug Discovery and Drug Development Divisions, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35255-5305, USA. a.tiwari@sri.org
Riordan
James M
JM
Waud
William R
WR
Struck
Robert F
RF
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010847:Picolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010847:Picolines; C034797:4-dimethylaminothymidine; C058388:penclomedine; D013936:Thymidine