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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (769)	12/30/2006 12:20:30 PM
From: tuck	Respond to of 933

[Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.] >>Chem Biodivers. 2004 Nov;1(11):1771-84. Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D. End N, Furet P, van Campenhout N, Wartmann M, Altmann KH. Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel. The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26), C(7)-C(12) (16), and C(13)-O(16) (19) of the macrocyclic framework. Construction of the C(12)-C(13) bond involved Pd(0)-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.<< I've had pubcrawler looking for epothilone D news for well over two years. But it just found this abstract from two years ago . . . or the actual publication date is very different from the one given in the abstract. Whatever, Novartis does some modeling, finds a promising lead. But they had some difficulty in getting a good yield, and the compound turned out to have no activity. So the authors, knowing they aren't giving away any secrets, publish to pad their resumes (Look, Ma! I can do total synthesis with Suzuki reactions!). It seems to underscore the difficulty with epothilones, and while Epo D may be kind of dead, it perhaps shows there is some value in Kosan's platform. Kosan at least got an Epo D out there with some activity, and were able to produce it with reasonable yields, while these big pharma guys basically whiffed. Cheers, Tuck

To: tuck who wrote (769)	6/29/2007 2:20:25 PM
From: tuck	Respond to of 933

[Small Molecule Inducers of Heat-Shock Response Reduce polyQ-Mediated Huntingtin Aggregation. A Possible Therapeutic Strategy] >>Neurodegener Dis. 2007;4(2-3):254-60. Small Molecule Inducers of Heat-Shock Response Reduce polyQ-Mediated Huntingtin Aggregation. A Possible Therapeutic Strategy. Herbst M, Wanker EE. Neuroproteomics Group, Max Delbrueck Center for Molecular Medicine, Berlin, Germany. Enhancing cellular defense mechanisms against different kinds of stress may be an attractive therapeutic strategy for neurodegenerative diseases. In particular, inducing the expression of molecular chaperones might reduce the formation of misfolded proteins and toxic aggregates that occur in polyglutamine (polyQ) disorders such as Huntington's disease. Geldanamycin, a natural substance that modulates Hsp90 function, was previously shown to induce a heat-shock response and to reduce polyQ aggregation in mammalian cells. However, because of toxic and unfavorable pharmacokinetic properties, geldanamycin is not suitable for clinical use. In this study we evaluated the effects of the pharmacologically improved geldanamycin derivatives 17-DMAG and 17-AAG on polyQ aggregation in mammalian cells. Quantitative RT-PCR and SDS-PAGE experiments revealed that 17-DMAG induces expression of the molecular chaperones Hsp40, Hsp70, and Hsp105 in mammalian cells and inhibits the formation of mutant huntingtin aggregates with higher efficiency than 17-AAG or geldanamycin itself. Induction of a heat-shock response and inhibition of polyQ aggregation occurred at nanomolar concentrations. We suggest that geldanamycin derivatives such as 17-DMAG should be considered for the development of a drug treatment for polyQ disorders and other neurodegenerative diseases involving protein aggregation.<< Again, not sure of the IP issues here. Cheers, Tuck