The proposed work involves the development of new amino-protecting groups and new coupling reagents for use in the synthesis of biologically active materials such as pharmaceuticals, polynucleotides, including PNAs, peptides, and small proteins. For ease of operation following the deblocking procedure, emphasis is placed on amino-protecting groups leading to (a) volatile, (b) infinitely water-soluble, or (c) easily-extracted by-products. Especially important are groups cleaved by mild organic bases or relatively non-basic nucleophiles under non-hydrolytic conditions. A large new class of protecting groups subject to deblocking under conditions of Michael addition typified by the Bsmoc function, will be studied in detail in terms of applicability to the synthesis of long-chain peptides or small proteins. The Bsmoc group will be examined for its application to (a) rapid, continuous syntheses in solution, (b) very rapid solid phase syntheses of longer peptides, and (c) peptides subject to base-catalyzed side reactions, such as peptide thio esters of possible use in new techniques for peptide ligation. Further studies on two new peptide-bond protecting groups, the Fm- and Dcpm functions, will probe applicability to problems of peptide insolubility and aggregation. Further optimization of new coupling systems based on 7-aza-1-hydroxybenzotriazole will be carried out, especially in the cases of HOAt-N-oxide and the azanaphthotriazoles. Mechanistic studies on the operation of these new coupling reagents will point the way to greater coupling efficiency and speed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM009706-37
Application #
6682907
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Schwab, John M
Project Start
1976-06-01
Project End
2004-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
37
Fiscal Year
2003
Total Cost
$307,000
Indirect Cost
Name
University of Massachusetts Amherst
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Carpino, Louis A; Nasr, Khaled; Abdel-Maksoud, Adel Ali et al. (2009) Dicyclopropylmethyl peptide backbone protectant. Org Lett 11:3718-21
Carpino, Louis A; Abdel-Maksoud, Adel Ali; Mansour, E M E et al. (2007) Segment Coupling to a Highly Hindered N-Terminal, Alamethicin-Related alpha-Aminoisobutyric Acid (Aib) Residue. Tetrahedron Lett 48:7404-7407
Carpino, Louis A; Abdel-Maksoud, Adel Ali; Ionescu, Dumitru et al. (2007) 1,1-dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (alpha-Nsmoc) and 3,3-dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (beta-Nsmoc) amino-protecting groups. J Org Chem 72:1729-36
McGinniss, M J; Kazazian Jr, H H; Stetten, G et al. (1992) Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21. Am J Hum Genet 50:15-28