Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-19
2002-05-21
Ramsuen, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S146000, C548S235000, C548S239000
Reexamination Certificate
active
06392055
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general to anti-cancer agents and more specifically to synthetic analogs of the antimitotic marine natural product curacin A.
BACKGROUND OF THE INVENTION
Natural products remain a significant source of promising lead structures for drug development. Cragg, G. M.; Newman, D. J.; Snader, K. M.
J. Nat. Prod.
1997, 60, 52; Shu, Y.-Z.
J. Nat. Prod.
1998, 61, 1053; Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem., Int. Ed.
2000, 39, 44. In recent years, an expansion of the structural diversity pool by preparation of libraries of natural products or natural product-like molecules has become a major focus of combinatorial chemistry. Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L.
J. Am. Chem. Soc.
1998, 120, 8565; Nicolaou, K. C.; Winssinger, N.; Vourloumis, D.; Oshima, T.; Kim, S.; Pfeffeirkorn, J.; Xu, J.-Y.; Li, T.
J. Am. Chem. Soc.
1998, 120, 10814; Meseguer, B.; Alonso-Diaz, D.; Griebenow, N.; Herget, T.; Waldmann, H.
Angew. Chem., Int. Engl.
1999, 19, 2902. After completion of the total synthesis of the strongly antimitotic Lyngbya majuscula metabolite curacin A in 1996 (Wipf, P.; Xu, W.
J. Org. Chem.
1996, 61, 6556), the inventors remained intrigued by the impressive antiproliferative profile (Verdier-Pinard, P.; Sitachitta, M.; Rossi, J. V.; Sackett, D. L.; Gerwick, W. H.; Hamel,
E. Arch. Biochem. Biophys.
1999, 370, 51; Gerwick, W. H.; Protear, P. J.; Nagle, D. G.; Hamel, E.; Blokhin, A.; Slate, D.
J. Org. Chem.
1994, 59, 1243) of this marine natural product and its potential use as a lead structure for the development of new synthetic tubulin polymerization inhibitors. For a review of agents that interact with the mitotic spindle, see: Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T.
Med. Res. Rev.
1998, 18, 259-69. For recent evaluations of small-molecule antimitotic agents, see: Haggarty, S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.; King, R. W.; Mitchison, T. J.; Schreiber, S. L.
Chem. Biol.
2000, 7, 275; Owa, T.; Okauchi, T.; Yoshimasa, K.; Sugi, N. H.; Ozawa, Y.; Nagasu, T.; Koyanagi, N.; Okabe, T.; Kitoh, K.; Yoshino, H.
Bioorg. Med. Chem. Lett.
2000, 10, 1223; Uckun, F. M.; Mao, C.; Vassilev, A. O.; Navara, C. S.; Narla, K. S.; Jan, S.-T.
Bioorg. Med. Chem. Lett.
2000, 10, 1015.
Compounds that inhibit cell proliferation are potentially useful in treating cancer, among other diseases. Curacin A is one such compound that inhibits cell growth and mitosis. See U.S. Pat. Nos. 6,057,348 and 5,324,739. Curacin A is believed to act by inhibiting microtubule processes associated with cell replication. It does this by binding to the colchicine-binding site, which is a relatively unique drug binding site.
Microtubules, the GTP hydrolysis-induced macromolecular assembly of &agr;/&bgr; tubulin heterodimers, are an indispensable cytoskeletal component. Intracellular microtubule arrays serve as the scaffold for support of the endoplasmic reticulum and as the railway by which organelles and vesicles are delivered by motor proteins in interphase cells. Mitosis is a four-stage process of cell division resulting in the production two identical daughter cells from a single parent cell. Not only are the daughter cells identical to each other, they are identical to the parent cell.
At mitosis, microtubules also serve as the cables through which force generated by motor proteins causes sister chromatids to segregate. Agents that alter the formation, stability and/or disassembly of microtubules typically arrest cell growth at the G
2
/M interface of the cell cycle, and may therefore be useful as antitumor agents. There are three major drug-interactive sites on tubulin. Two of these are the basis of clinically useful antitumor agents. The paclitaxel site on &bgr;-tubulin is bound by paclitaxel and docetaxel, which stabilize microtubules against disassembly. The vinca domain, bound by agents such as vinblastine, vincristine and vinflurabine, which inhibit proper assembly of tubulin heterodimers into microtubules, is at an incompletely elucidated region of the heterodimer.
A third major class of microtubule perturbing agents bind to the colchicine site, which appears to be largely or exclusively on &bgr;-tubulin, but may include regions of the &agr;/&bgr; interface. Agents that bind to the colchicine site appear to have affinity for unassembled &agr;/&bgr; heterodimers. Until recently, all agents with known affinity for the colchicine site could be described as biaryl systems with appropriate substituents linked by short alkyl/alkenyl chains. The only useful pharmacological actions of colchicine site agents have been in the treatment of inflammatory processes. Discovery of the antitumor and associated antiangiogenesis actions in animal models of some colchicine site agents (e.g. 2-methoxyestradiol, combretastatin A-4 phosphate) suggest, however, that perturbation via this domain may yet prove useful for cancer treatment.
The discovery that curacin A and some of its closely related analogs bind the colchicine site with high avidity and are potent antimitotic agents caused a reevaluation of the biaryl systems theory. Early structure-activity relationship studies with curacins indicate that the parent structure is very intolerant of modification.
Curacin A exhibits anticancer properties similar to paclitaxel. Like paclitaxel, curacin A comes from a natural source. Both compounds exhibit a remarkable ability to disrupt cell mitosis, thereby inhibiting cell proliferation. This antimitotic ability makes these compounds potentially promising in treating cancer. In the case of both paclitaxel and curacin A, the trend is towards developing methods of synthesizing analogs that exhibit greater biological activity than the naturally derived compounds. Additionally, these methods should be more efficient than deriving the compounds from natural sources. As such, it is highly desirable to find ways of synthesizing more stable and biologically active analogs of curacin A.
According to several reports, curacin A promotes arrest of the cell cycle at the G
2
/M checkpoint and competitively inhibits the binding of [
3
H]-colchicine to tubulin, and it can therefore be considered a colchicine site agent. Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T.
Med. Res. Rev.
1998, 18, 259-69; Verdier-Pinard, P.; Lai, J.-Y.; Yoo, H.-D.; Yu, J.; Marquez, B.; Nagle, D. G.; Nambu, M.; White, J. D.; Falck, J. R.; Gerwick, W. H.; Day, B. W.; Hamel, E.
Mol. Pharmacol.
1998, 53, 62. In addition to a large number of total syntheses of curacin A, the attractive biological properties of this compound have led to numerous biological studies. For discussion of curacin A syntheses, see: White, J. D.; Kim, T.-S.; Nambu, M.
J. Am. Chem. Soc.
1995, 117, 5612; Hoemann, M. Z.; Agrios, K. A.; Aube, J.
Tetrahedron Lett.
1996, 37, 935; Ito, H.; Imai, N.; Takao, K.; Kobayashi, S.
Tetrahedron Lett.
1996, 37, 1799; Onada, T.; Shirai, R.; Koiso, Y.; Iwasaki, S.
Tetrahedron Lett.
1996, 37, 4397; Lai, J.-Y.; Yu, J.; Mekonnen, B.; Falck, J. R.
Tetrahedron Lett.
1996, 37, 7167; White, J. D.; Kim., T.-S.; Nambu, M.
J. Am. Chem. Soc.
1997, 119, 103; Hoemann, M. Z.; Agrios, K. A.; Aube,
J. Tetrahedron
1997, 53, 11087; Muir, J. C.; Pattenden, G.; Ye, T. Tetrahedron Lett. 1998, 39, 2861. However, even minor changes in the structure of curacin A can lead to essentially inactive derivatives. Verdier-Pinard, P.; Lai, J.-Y.; Yoo, H.-D.; Yu, J.; Marquez, B.; Nagle, D. G.; Nambu, M.; White, J. D.; Falck, J. R.; Gerwiek, W. H.; Day, B. W.; Hamel, E.
Mol. Pharmacol.
1998, 53, 62; Marquez, B.; Verdier-Pinard, P.; Hamel, E.; Gerwick, W. H.
Phytochemistry,
1998, 49, 2387; Nishikawa, A.; Shirai, R.; Koiso, Y.; Hashimoto, Y.; Iwasaki, S.
Bioorg. Med. Chem. Lett.
1997, 7, 2657; Martin, B. K. D.; Mann, J.; Sageot, O. A.
J. Chem. Soc., Perkin Trans.
1, 1999, 2455; Onoda, T.; Shirai, R.; Koiso, Y.; Iwasaki, S.
Tetrahedron
1996, 52, 14543; Blokhin, A. V.; Yoo, H. D.; Geralds, R. S.; Nagle, D. G.;
Balachandran Raghavan
Day Billy W.
Reeves Jonathan T.
Wipf Peter
D'Souza Small Andrea
Ramsuen Robert W.
The University of Pittsburgh
Thorp Reed & Armstrong LLP
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