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Mahesh Lakshman Ph.D.

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Mahesh Lakshman, Ph.D.

Organic Chemistry


Email:
Office Phone: (212) 650-7835

Education:

  1. BSc University of Bombay (now Mumbai)
  2. MSc University of Bombay (now Mumbai)
  3. MS University of Oklahoma
  4. PhD University of Oklahoma

Biography:

Cancer & Immunology Research @ CCNY


ORGANIC SYNTHESIS AT THE CHEMISTRY BIOLOGY INTERFACE


    Research in our group primarily involves development of novel organic synthesis techniques to address questions of a biological nature.  Current research projects are directed in two major directions: studies on understanding the molecular basis of chemical-induced mutagenesis as well as carcinogenesis, and metal-mediated nucleoside modification methods.

Studies on site-specific DNA modification with metabolites of polycyclic aromatic hydrocarbons

    Polycyclic aromatic hydrocarbons (PAHs) as well as their aza and sulfur analogs are widely prevalent in the environment and many members of this family are metabolized to ultimate carcinogens.  These compounds therefore represent a health risk to humans.  The metabolically formed compounds that cause adverse biological effects are the 4 isomeric bay or fjord region diol epoxides shown in Figure 1.

Figure 1
    All 4 diol epoxides interact with DNA and undergo a ring-scission of the epoxide moiety and the ensuing cationic intermediate is trapped by the exocylic amino groups of the purine bases in cellular DNA.  This covalent modification of DNA is considered to be the first step in the mutagenic and carcinogenic responses eliced by the diol epoxides.  Since the overall mechanism of DNA alkylation is SN1 like, each diol epoxide can produce 4 nucleoside adducts with each of the 2 purine nucleosides.  Thus, metabolism and DNA binding of any single PAH can result in the formation of a total 16 adducts.  The biological effect of each adduct must then be related to the replication and repair mechanisms involved (Figure 2).
 
 
 
Figure 2
  
    In order to understand better the biochemical processes involved in mutagenesis by diol epoxide-DNA adducts, research in our group is directed towards the stereoselective synthesis of individual diol epoxide-nucleoside adducts and incorporation of these into specific sites in DNA.  This entails in most cases development of new synthesis methodology.  Once the site-specifically modified DNA are available, then a variety of physical measurements can be undertaken, as well as determination of their solution structures by NMR.  Experimentation in collaboration with biochemists is aimed at understanding the cellular process that can then be related to the structures of the specific diol epoxide-DNA lesion.  Structures of the various DNA adduct stereoisomers are shown in Figure 3.
Figure 3


Influence of molecular structure on the biological properties of aromatic hydrocarbons

    There has been a proposal that non-planarity of polycyclic aromatic hydrocarbons may influence their DNA adduct forming abilities and the net biological effect of the DNA adducts.  Therefore, our group has been interested in the synthesis of non-planar PAHs as well as their metabolic profiles and biological activities.  In this context we have synthesized 1,4-dimethylbenzo[c]phenanthrene (1,4-DMBcPh) and its metabolites. This PAH is 35 degrees out of plane (Figure 4) compared to the unsubstituted benzo[c]phenanthrene (BcPh, which is 25 degrees out of plane).

Figure 4

    Our studies have shown that 1,4-DMBcPh and its putative metabolites exhibit helical properties and the isomers undergo slow helical interconversion (Figure 5).  In addition, 1,4-DMBcPh is less readily oxidized to its terminal diol epoxide metabolites by cytochrome P450 1B1 and metabolic activation in the final epoxidation step is substantially influenced by the distortion in the molecule.

Figure 5

Departments:

Chemistry & Biochemistry:
Associate Professor