Antitumor compounds based on a natural product consensus pharmacophore.
We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous novel analogues. We present results on the in vitro activity for this compound against several tumor cell lines.
Lagisetti
Chandraiah
C
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Pourpak
Alan
A
Jiang
Qin
Q
Cui
Xiaoli
X
Goronga
Tinopiwa
T
Morris
Stephan W
SW
Webb
Thomas R
TR
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001685:Biological Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D001685:Biological Factors; D004852:Epoxy Compounds; C104486:FR 901464; D018942:Macrolides; D011714:Pyrans; D013141:Spiro Compounds; C522342:pladienolide B
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