In our laboratory we seek to study potential advances in organic synthesis and to apply such advances to the elaboration and study of natural products or natural product congeners of novel biological activity. In HL 25848, we will be engaged in projects at 2 levels. A group of new targets which fall broadly in the category of non-peptidyl neurotrophic factors has been identified for total synthesis studies as well as SAR follow-up studies using what we term as diverted total synthesis (vide infra). Our goal is to have at our disposal, through total synthesis, a focused library of small molecules with neurotrophic activity. We hope that these synthesis programs, in the context of functional collaborative bio-mechanistic studies, will lead to real progress in the understanding and treatment of neurodegenerative diseases. The new targets directed to this motif include (i) scabronine G methyl ester, a cyathane diterpene; (ii) spirotenuipesine A, a novel spirocyclic trichothecane; (iii) 11-O-debenzoyltashironin; (iv) terreulactone; (v) tricholomalide A; and (vi) the 2 antipodes of merrilactone A. In addition, in this grant period, we hope to bring to closure several goal systems from the 22-26 interval. These include: (vii) phomactin A, a potent PAF antagonist; (viii) xestocyclamine, a novel and highly active PKC inhibitor; and 2 complex antitumor isoquinolinoid alkaloids, (ix) ecteinascidin-743 and (x) cribrostatin IV. In each case where the natural product target has been shown to exhibit promising and useful activity, there will be focused, well-aimed collaborative biological follow-up studies seeking to provide mechanistic insights to augment functional assays and to evaluate potential for further development.
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