Subject(s)
Antineoplastic Agents/chemistry , Phenazines/chemistry , Pyrazines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Phenazines/chemical synthesis , Phenazines/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Steroids/chemical synthesis , Steroids/chemistry , Structure-Activity RelationshipABSTRACT
We are developing methods that restrict the conformational mobility of peptides and related heteropolymers while simultaneously altering their properties. Our experiments occur as processes wherein a conserved, lipophilic reagent is activated in stages to form composite products with unprotected polyamides in parallel. For each starting oligomer, the goal is to create not one, but rather a collection of products. The intent is for those materials to retain molecular recognition elements of the biopolymer, yet display that functionality as part of stable, cyclic structures having defined shapes and enhanced membrane solubility/permeability. Here we describe reagent 2 and its two-step integration into peptides to afford macrocyclic ethers (e.g., 4 when starting with W-W-Y). When those materials are treated with protic acid in anhydrous solvent, the cinnamyl unit migrates from the oxygen of tyrosine to distribute throughout the structure, forming new products via carbon/carbon bonding. These changes occur concomitantly with acid-promoted rearrangements/cyclizations of the dienyne appendage to generate mixtures containing unique macrocycles such as 15. Similar amalgamations of 2 with more diverse peptides is a means to begin accessing complex peptidomimetics systematically. From a library of screening fractions generated in this way, we have identified a small molecule that selectively promotes hippocampal neurogenesis in the adult mouse brain.
Subject(s)
Acids/chemistry , Cinnamates/chemistry , Macrocyclic Compounds/chemical synthesis , Peptides/chemistry , Animals , Cell Proliferation/drug effects , Cyclization , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Ions/chemistry , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Mice , Molecular Conformation , Polymers/chemistry , StereoisomerismABSTRACT
Oxidative functionalization (or removal) of a steroidal C18 methyl group is possible using a previously unknown dyotropic rearrangement of a seven-membered fused C-ring lactone to a 6-ring spiro lactone. Spiroketal equilibration led to the 23-deoxy South analogue of cephalostatin 1 (1) in only 12 steps (23% overall yield) from hecogenin acetate 4, and to strained diene South 1 analogue 30 in 11 steps (28% overall). Total synthesis of 23'-deoxy cephalostatin 1 (3) was accomplished in 16 operations from 4 (9% overall; average 86% yield per operation), and that of 16',17'-dehydro-23'-deoxy cephalostatin 1 (36) in 15 operations from 4 (8% overall; av 84%/op).
Subject(s)
Phenazines/chemical synthesis , Spiro Compounds/chemical synthesis , Steroids , Oxidation-Reduction , Phenazines/chemistry , Spiro Compounds/chemistry , Spironolactone/analogs & derivatives , Spironolactone/chemical synthesis , Spironolactone/chemistry , StereoisomerismABSTRACT
The structure of the North spiroketal moiety of ritterazine M has been corrected from 1a to 1b. This was accomplished by comparison of published spectra of the natural product with five synthetic spiroketal-alcohols. Synthesis of these models was efficiently accomplished by reductive cleavage of the spiroketal and Sharpless asymmetric dihydroxylation of an isopentyl, methyl 1,1-disubstituted olefin, followed by Suarez iodine[III] oxidative spirocyclization of monoprotected 1 degree,3 degree 1,2 diols.
