Integrin-Targeting 38C2 Constructs
Using antibody 38C2 and antagonists of αvβ3/αvβ5 integrins, we produced several antagonist-38C2 conjugates. These conjugates bound efficiently to cells expressing αvβ3/αvβ5 and inhibited the growth of several cancerous tumors in animal models. This research was done in collaboration with C.F. Barbas, the Skaggs Institute. In continuation, we produced additional 38C2 constructs that target αvβ3 integrins and evaluated the constructs in the breast cancer cell lines MDA-MB-435 and MDA-MB-231. The new constructs are more selective that the older ones and bind to αvβ3 integrins. We are evaluating the features of new constructs. This research was done in collaboration with B. Mueller, La Jolla Institute for Molecular Medicine, San Diego, California.
Hyperglycemia is the cause of most complications
associated with diabetes mellitus. To prevent or reduce the complications, patients with diabetes
often require multiple insulin injections daily. Alternatively, a closed-loop system of regulated
insulin delivery in response to elevated blood glucose levels can be constructed by using insulin
prodrugs. We synthesized 2 insulin prodrugs (Fig. 2) and evaluated their ability to stimulate
glucose uptake in an in vitro system.
The prodrugs were minimally active in the protected state but become active after photolysis with 365-nm light. Thus, they have potential for use in an implantable closed-loop device, coupling a glucose sensor to a small ultraviolet lamp to photoactivate and release the correct dose of insulin in response to elevated glucose levels. This work was done in collaboration with J. Olefsky, University of California, San Diego.
Synthesis of Sorangiolides and Bis-Tetrahydrofuran Acetogenins
Sorangiolides A and B, naturally occurring
macrocyclic molecules (Fig. 3), are weakly active against gram-positive bacteria. As a first
step to producing more active analogs of these molecules, we synthesized the naturally occurring
macrolides. The key steps in the synthesis of these compounds include the Suzuki-Fu reaction,
the 1,5-induction in the stereoselective aldol reaction developed by Evans, and the macrolactinization
reaction. To synthesize a complete library of bis-tetrahydrofuran annonaceous acetogenins,
we have developed a bidirectional approach for the synthesis of all 64 diastereomers of the adjacent
bis-tetrahydrofuran acetogenins (Fig. 3).
Starting with 8 diene lactones, we synthesized 36 bifunctional adjacent bis-tetrahydrofuran lactones by using 5 key reactions: (1) monooxidative or bis-oxidative cyclization mediated by rhenium(VII) oxides, (2) Shi monoasymmetric or bis-asymmetric epoxidation, (3) Sharpless asymmetric dihydroxylation, (4) Williamson-type etherification, and (5) Mitsunobu inversion. Starting with a bis-tetrahydrofuran lactone, we synthesized 2 nonnatural bullatacin analogs.
Das, S., Li, L.-S., Abraham, S., Chen, Z., Sinha, S.C. A bidirectional approach to the synthesis of a complete library of adjacent-bis-THF annonaceous acetogenins. J. Org. Chem. 70:5922, 2005.
Li, L.-S., Babendure, J.L., Sinha, S.C., Olefsky J.M., Lerner, R.A. Synthesis and evaluation of photolabile insulin prodrugs. Bioorg. Med. Chem. Lett. 15:3917, 2005.
Saphier, S., Hu, Y., Sinha, S.C., Houk, K.N., Keinan, E. Origin of selectivity in the antibody 20F10-catalyzed Yang cyclization. J. Am. Chem. Soc. 132:127, 2005.