In my laboratory, we predominantly synthesize drugs and analyze them on purity and identity and redox properties. Such properties, based on our 2 decade-long expertise allow us to predict which drug is perspective to be forwarded towards clinic. The details of our research are listed below, under current projects. The research is very successful, all previous and present postdocs on average are able to publish ~5 papers per year of dedicated work in my Lab in highly cited Journals. All of my previous postdoc got academic positions upon completing postdoc in my lab.
- Design, synthesis and characterization of highly active metal based redox modulators.
Based on established structure-activity relationships, the lab is constantly engaged in design and synthesis of novel redox active, highly bioavailable and less toxic agents. Along with these investigations, new, more efficient methods of preparation and purification are being developed to assure the quality of compounds applied in in vivo experimental, as well as in mechanistic studies.
- Investigation of pharmacokinetic profile of Mn porphyrin based SOD mimcs.
Novel methods have been developed based on LCMS/MS technique that enables us to conduct the comprehensive pharmacokinetic studies of Mn(III) N-substituted pyridylporphyrins. Numerous in vivo experiments with these compounds are now in progress and investigation of their PK/tox profile, bioavailability via various administration routs (og, iv, sc, or ip) are of critical importance.
- Investigation of anticancer mechanism of action of Mn porphyrin based redox modulators.
Investigations are in progress to evaluate the anticancer potential of Mn porphyrins alone or in combination with radiation and chemotherapeutics. Preliminary data show that Mn porphyrins are able to enhance the effect of radiation and temozolomide in brain glioma in vivo models. The mechanism has been proposed and is related to oxidative modification of thiols and will be further evaluated in different models.
- Evaluation of radioprotective effect of Mn porphyrins. Collaborative studies are done with Dr. Dewhirst at Duke University on whole brain radioprotection (and is a part of Brain SPORE) and with Dr. Huang at Stanford University, and Dr. Beausejour at University of Canada. Also a very prospective studies related to radioprotection of prostate and reversal of radiation-caused erectile dysfunction are conducted with Dr. Oberley at University of Colorado and Dr. Koontz at Duke University.
- Mechanistic studies of the effects of Mn porphyrins/ascorbate system are conducted on inflammatory breast cancer in collaboration with Dr. Devi and are already showing effects which have been described in manuscript under revision in Free Radic Biol Med.
- Investigation of Fe porphyrins in stroke therapy.
The efficacy of Mn porphyrins in stroke therapy was previously well documented. However, due to their strong hypotensive effect on blood pressure, Mn porphyrins allow for small therapeutic window. Our recent studies showed that Fe porphyrins are of similar redox potency (determined as log kcat(O2.-) as their Mn counterparts, yet with no effect on blood pressure. Hence, the study on efficacy of Fe porphyrins in stroke model is currently in progress and supported by NIH R03 grant.
- Investigation of interaction of metalloporphyrins with various redox active agents.
We have demonstrated that Mn porphyrins are able to interact/redox cycle with ascorbate, tetrahydrobiopterin, thiol-containing compounds, such as cysteine, dithiothreitol, glutathione, N-acetyl cysteine, protein thiols, etc. The interaction leads to the formation of cytotoxic hydrogen peroxide which seems to be heavily involved in defying the destiny of cancer cell: to dye or to proliferate. Employing such systems in in vitro and in vivo settings we are studying the anticancer potential of the combinations of Mn porphyrins with cellular reductants.
This project involves also the collaborative studies with Dr. Leong on preparing delivery systems directly into tumor which would utilize the excessive production of cytotoxic peroxide to kill tumor in situ – we have just applied for funding.
- We are constantly and routinely studying the SOD-like activity of metalloporphyrins which parallels their therapeutic potential, log kcat(O2.-). We are also constantly determining metal-centered reduction potential of such compounds, E1/2. The log kcat(O2.-) and E1/2 are major parameters that up-front enable us to evaluate our compounds as drug candidates. Along with SOD-deficient E. coli and yeast S. cerevisiae studies with our major collaborator. Dr Benov we can safely estimate the lead candidates for cellular, animal and human studies.
- We are conducting stroke, spinal cord, subarachnoid hemorrhage and pain studies in collaboration with Dr. David Warner and Dr. Huaxin Sheng at Department of Anesthesiology for already 15 years. We are awarded DOD grant on spinal cord injury where we recently demonstrated remarkable efficacy of our drugs.
- We are synthesizing new drugs, such as fluro-derivatized, the research supported by BioMimetix Pharmaceutical, Inc.