Antitumor agents. 139. Synthesis and biological evaluation of thiocolchicine analogs 5,6-dihydro-6(S)-(acyloxy)- and 5,6-dihydro-6(S)-[(aroyloxy)methyl]-1,2,3-trimethoxy-9-(methylthio)-8H- cyclohepta[a]naphthalen-8-ones as novel cytotoxic and antimitotic agents.
A series of novel thiocolchicine analogs, 5,6-dihydro-6(S)-(acyloxy)-and 5,6-dihydro-6(S)-[(aroyloxy)-methyl]-1,2,3-trimethoxy-9-(methylthi o)-8H- cyclohepta[a]naphthalen-8-ones, possessing a six-membered ring B, have been synthesized and evaluated for their cytotoxicity against various tumor cell lines, including solid tumor cell lines, and for their interaction with tubulin. The configuration of the parent alcohol (compound 5) was established unequivocally as (aR,6S) by X-ray crystallographic analysis. The side chain at the C(6) position is in a pseudoaxial orientation. The optical properties and 1H NMR data indicated that these compounds have the same conformations in solution as in the solid state. Biological results showed that compounds (5, 6, 14, 15, 17, and 18) bearing a small side chain at C(6) demonstrate high potency in inhibiting tubulin polymerization and binding of radiolabeled colchicine to tubulin. The most cytotoxic compounds were 14, 15, 17, and 18, with good activity against several solid tumor cell lines. To explain the strong antitubulin activity of compound 5 (with an aR configured biaryl system in contrast to the aS configuration previously described for colchicinoids, allocolchicinoids, and steganacin) we speculate that a rapid atropisomerism equilibrium must exist for 5 and its active derivatives. This equilibrium would yield adequate amounts of aS-configured conformers that interact, strongly with tubulin. Since the optically inactive 18 is also a potent inhibitor of tubulin, the configuration of the side chain of these six-membered ring B analogs cannot be essential for their binding to tubulin. Instead we propose that the size of ring B and of its side chain play important roles in tubulin binding activity by affecting the rotation of the rings A and C along their linking C-C bond axis.
Sun
L
L
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
McPhail
A T
AT
Hamel
E
E
Lin
C M
CM
Hastie
S B
SB
Chang
J J
JJ
Lee
K H
KH
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002417:Cattle; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators; C014856:thiocholchicine; D006160:Guanosine Triphosphate; D003078:Colchicine