Laulimalide derivatives

Details Laulimalide derivatives Laulimalide derivatives

2003-02-10

2004-11-09

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S451000, C514S452000, C514S453000, C514S456000, C514S560000, C540S488000, C549S267000, C549S268000, C549S269000, C549S270000, C549S271000

Reexamination Certificate

active

06815463

ABSTRACT:

BACKGROUND
Laulimalide (1) and isolaulimalide (2), also known as fijianolides, were originally isolated as cytotoxic agents from the Indonesian sponge
Hyatella
sp. (E. Quinoa et al., “Fijianolides, polyketide heterocycles from a marine sponge,”
J. Org. Chem.,
1988, 53, 3642; D. G. Corley et al., “Laulimalides. New potent cytotoxic macrolides from a marine sponge and a nudibranch predator,”
J. Org. Chem.
1988, 53, 3644-3646), and later found along with neolaulimalide (3) in the Okinawan sponge
Fasciospongia rimosa
(Jefford et al., “Structures and absolute configurations of the marine toxins, latrunculin A and laulimalide,” 1996,
Tetrahedron Letts.
37: 159-162; Higa et al., “Three new cytotoxic macrolides from a marine sponge,” PCT publication No. WO 97/10242). The absolute structure of natural (−)-laulimalide has been determined by X-ray crystallography.
A number of total syntheses of laulimalide have been reported. See Ghosh et al., 2001, “Total synthesis of microtubule-stabilizing agent (−)-laulimalide,”
J. Org. Chem.
66: 8973-8982; Paterson et al., 2001, “Total synthesis of microtubule-stabilizing agent (−)-laulimalide,”
Org. Letts.:
3149-3152; Enev et al., 2001, “Macrocyclization via allyl transfer: total synthesis of laulimalide,”
J. Am. Chem. Soc.
123: 10764-10765; Ghosh et al., 2000, “Total synthesis of (−)-laulimalide,”
J. Am. Chem. Soc.
122: 11027-11028.
A mechanism-based screening program aimed at isolating novel microtubule-directed anticancer agents revealed both laulimalide and isolaulimalide to be potent stabilizers of microtubules, similar to paclitaxel. See S. Mooberry et al., 1999,
Cancer Res.,
59, 653-660; Mooberry & Davidson, “Laulimalide compounds as microtubule stabilizing agents,” PCT Publication No. WO 01/54689, incorporated herein by reference.
Because of the problems associated with the use of paclitaxel such as low solubility and resistance, there is an increasing need for alternative anti-cancer compounds. The present invention provides such compounds.


REFERENCES:
patent: 6414015 (2002-07-01), Mooberry et al.
patent: WO 97/10242 (1997-03-01), None
patent: WO 01/54689 (2001-08-01), None
Corley et al., J. Org. Chem. (1988) 53:3644-3646.
Enev et al., J. Am. Chem. Soc. (2001) 123:10764-10765.
Ghosh et al., J. Am. Chem. Soc. (2000) 122:11027-11028.
Ghosh et al., J. Org. Chem. (2001) 66:8973-8982.
Jefford et al., Tetrahedron Letts. (1996) 37:159-162.
Mooberry et al., Cancer Res. (1999) 59:653-660.
Paterson et al., Org. Letts. (2001) 3(20):3149-3152.
Quinoa et al., J. Org. Chem. (1988) 53:3642.
Pryor, et al., “The Microtubule Stabilizing Agent Laulimalide Does Not Bind in the Taxoid Site, Kills Cells Resistant to Paclitaxel and Epothilones, and May not Require Its Epoxide Moiety for Activity,”Biochemistry(2002) vol. 41, No. 29, 9109-9115.

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