The objectives of this project are to develop an efficient synthesis of the recently discovered molecule lactonamycin and to prepare analogs of it that optimize its biological activity. Lactonamycin's hexacyclic structure is unlike that of any other compound. It exhibits potent activity against bacteria resistant to existing antibiotics including methicillin-resistant (MSRA) and vancomycin-resistant (VRE) strains. Lactonamycin also possesses significant anticancer activity. In the course of our work we intend to explore new general strategies for achieving stereo-, regio-, and enantioselective transformations.
The specific aims are: To develop a short and efficient synthesis of lactonamycin. To use that effort as an opportunity to explore new general strategies for accomplishing stereo-, regio-, and enantiocontrolled synthetic transformations including (i) extending the role of intramolecular hydrogen bonding and/or borate complexation in Diels-Alder reactions, (ii) developing a dynamic thermodynamic (as opposed to kinetic) resolution, and (iii) examining new ligands for controlling intramolecular delivery of OsO4 under circumstances where Sharpless-type asymmetric dihydroxylation is expected to fail. To employ the synthetic route to prepare analogs of lactonamycin with the aim of (i) making available water-soluble derivatives of lactonamycin, (ii) separating and optimizing the antibiotic and antitumor activities, (iii) identifying the pharmacophores, and (iv) beginning SAR studies. To test, in collaboration with Pfizer Inc., analogs and synthetic intermediates for antibiotic, anticancer and other biological activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061980-04
Application #
6636522
Study Section
Special Emphasis Panel (ZRG1-SSS-A (02))
Program Officer
Schwab, John M
Project Start
2000-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$268,515
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Kelly, T Ross; Cai, Xiaolu; Tu, Bin et al. (2004) Asymmetric synthesis of the AB ring system of lactonamycin. Org Lett 6:4953-6
Kelly, T Ross; Xu, Dongcheng; Martinez, Gabriel et al. (2002) Short synthesis of the CDEF ring system of lactonamycin. Org Lett 4:1527-9