Synthesis of biologically active molecules
Our approach to rational drug design uses our knowledge of macromolecular structure and the modes of action of known biologically active small molecules to design new molecules with potent biological activity. Several examples are shown below.
Novel Antitumor Analogues of Neocarzinostatin Chromophore
The antitumor antibiotic neocarzinostatin chromophore (NCS, 1) has been shown to cleave DNA by a novel cycloaromatization (the "Myers cyclization") induced by nucleophilic attack on the strained unsaturated core (Scheme 1). The indenyl diradical formed by this cascade (3) cleaves DNA through hydrogen atom abstraction from a ribose ring of the DNA backbone. This mechanism is very similar to that of the related ene-diyne antibiotics and represents a potentially important means of treating certain solid tumors.
Scheme 1
Although attractive as an antitumor antibiotic lead candidate, NCS is too complex to synthesize easily. It is our goal to develop easily synthesized, small molecule analogues for testing for cytotoxicity against tumor cell lines. To do this, we have developed an anionic Myers cyclization (Scheme 2) that we hope will permit ready access to numerous NCS analogues [Ref. 6]Current efforts in the group are directed toward synthesizing and assaying analogues of the prototype 4. Future work will focus on determining the cytotoxicity of the best candidates against selected tumor cell lines.
Scheme 2
New Approaches to AIDS Therapy
Current approaches to the treatment of AIDS have focused on two of the requisite three enzymes found in HIV-1, the virus responsible for AIDS. An alternate approach was outlined in a publication by Sandoz in 1994, in which they demonstrated that the clinical immunosuppressant cyclosporin A (CSA, 5) inhibited the formation of infectious HIV-1 virions through a novel mechanism: inhibition of a cellular enzyme (cyclophilin A, CyP) that is required for packaging of intact HIV-1 particles. While the role of CyP is still a subject of some debate, it is known that CyP catalyzes the isomerization of tertiary amides from trans to cis (Scheme 3) and that CSA is a nanomolar inhibitor of this activity.
Cyclosporin A (5)
Scheme 3
While CSA is impractical as an AIDS therapeutic owing to its immunosuppressant activity, small molecule inhibitors of CyP represent a completely new approach to the treatment of AIDS. We are pursuing the development of potent CyP inhibitors through a combination of molecular modeling, synthesis and in vivo assay. We have also used a new peptide backbone modification developed in our laboratories to synthesize a potential inhibitor of HIV-1 protease (6), currently one of the two most important therapeutic targets for AIDS therapy.
6
Structure-Activity Studies on Cytotoxic Marine Depsipeptides
Two cytotoxic marine cyclic depsipeptides, callipeltins A (7) and B (8) were isolated and characterized by a group in the University of Naples in 1996. Both of these molecules display potent cytotoxicity against selected tumor cell lines, but callipeltin A also displays antifungal and anti-HIV activity. Although the individual amino acid residues were all identified, the configuration of the B-methoxytyrosine residue highlighted in the structures could not be identified. We have recently undertaken the total synthesis and structure identification of 7 and 8 using a solid phase synthesis approach.
Callipeltins A (7) and B (8)
Future work in this area will focus on determining the mode of action of 7 and 8 and on the synthesis and study of synthetic analogues. Questions that we hope to answer are:
- How do these molecules kill cancer cells and fungi?
- Are the two modes of action the same?
- What are the roles of the unnatural amino acids found in 7 and 8?
- Can useful activity be found in smaller analogues of 7 and 8?
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