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David P. Brown
Design and Synthesis of Natural Product Hybrids as New Chemical Entities in Drug Discovery and Development
One of the terminal objectives of organic synthesis from its very inception has been the search for new compounds that exhibit novel physical, chemical and biological properties. Such new compounds have undoubtedly saved countless human lives, alleviated pain and suffering, extended human longevity, and has positively impacted the global economy. In spite of the miraculous breakthroughs however, society continues to be faced with numerous challenges arising in part from drug resistance, the emergence of new forms of cancers, and the surfacing of new strains of microbial pathogens.
In this quest for biologically active new chemical entities, both human intuition and leads from Nature have played pivotal roles. Nature makes natural products of mystifying diversity and complexity and these are generally derived through specific biosynthetic pathways leading to a particular class of compounds with specialized functions. Accordingly, humanity has learned to harness natural sources for the vast majority of bioactive compounds in medical use today. Approximately 40% of the drugs that have been approved are either natural products or derivatives and analogues thereof. Among anticancer and anti-infective agents, the percentage is even estimated to exceed 70%, including such well-known examples as penicillin G and paclitaxel (taxol). Indeed, organ transplantation, one of the major miracles of modern medicine, would not have been possible without immunosuppressive natural products such as cyclosporin A and rapamycin.
Our current research efforts are geared toward a further harnessing of nature’s structural variety by combining two or more natural products to form hybrids. The anticipated outcome is to generate new chemical entities with enhanced characteristics, particularly the therapeutic spectrum, based on natural product leads. Synthesis of such entities typically involves intricate synthetic manipulations for structural integration or simple straightforward manipulation of functional groups.
In one approach, a series of hybridized systems with a steroidal substructure are being generated. The selection of a steroidal nucleus as the base for these systems stems from the established precedence that the estrogen receptor is present in higher concentrations in carcinogenic tissues (breast, ovarian, prostatic and endometrial) than in normal tissues. Accordingly, estrogens have been investigated as vectors for cytotoxic agents in the hope that an increased organ and/or tissue specificity can be achieved through a selective accumulation of the cytotoxic compound in tumor cells. Novel systems include hybrids of estradiol and combretastatin A4, estradiol and various substituted beta-lactams, and estradiol with phenstatin systems.
In another approach, novel fatty acid conjugates are being developed as new microtubule-binding drug candidates for cancer chemotherapy, contributing to the ongoing efforts directed toward the development of alternate treatment options in cancer chemotherapy. More specifically, new anti-cancer compounds are being generated that are designed to be more target specific, while simultaneously exhibiting reduced side effects. Additionally, these novel compounds will serve as new leads in addressing the multidrug resistance (MDR) barrier that limits current treatment protocols and programs.
Figure 1: Hybrids of Combretastatin-A4
The PUFA conjugates are being generated by chemically linking various naturally occurring poly-unsaturated fatty acids (PUFAs) with known anti-cancer molecules. In addition to enhancing the therapeutic profile of the anti-tumor compound, the incorporated fatty acid will render the conjugate more likely to be internalized and retained by tumor cells. Considering the possibility for premature enzymatic cleavage of some conjugates, different chemical links of varying strengths and chemical properties are being employed in connecting the fatty acids to the anti-tumor molecules. Two sequences of conjugates are being generated; one based on Phenstatin, and the other based on Combretastatin-A4. Each new conjugate will subsequently be evaluated in vitro against various human tumor cell lines to determine their relative anti-proliferative properties. Based on the unique structure of the incorporated fatty acid, a range of biological activities is anticipated. Thus, the most active compounds will be targeted for further pre-clinical investigations, while the less active derivatives will serve as leads in the development of new MDR reversal agents.
Figure 2: Phenstatin PUFA Conjugates
Initial investigations have established the proof-of-principle that conjugate activity is directly related to the degree of unsaturation of the incorporated fatty acid.
Figure 3: Cytotoxic effects of PUFA Conjugates on MCF-7 cells
A third area of investigation involves the design and synthesis of new substrate inhibitors of the enzyme PlsY, the key bacterial glycerol-phosphate acyltransferase which plays a pivotal role in the synthesis of phosphatidic acid, the intermediate in membrane phospholipid biosynthesis. Membrane phospholipid synthesis is a vital facet of bacterial physiology making the associated enzymes attractive targets for the development of bactericidal agents particularly for Gram-positive pathogens. In this quest, novel derivatives of readily available and FDA-approved polyols and various bioactive groups are being developed as potential candidates towards the “10 x 20 Initiative” of the Infectious Diseases Society of America (IDSA) – Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020.
Figure 4: PlsY Substrate Inhibitors
Brown, D. P., Zhao, H., Khondoker, J., Bhavsar, J., and Sigamoney, S.; “Synthesis of Novel b-lactam Hybrids of Phenstatin and Other Substituted Aromatics as New Bioactives”, Heterocycles, 2014, 89, 2380-2391.
Chen, J., Brown, D. P., Wang, Y. and Chen, Z.; “New phenstatin fatty acid conjugates: synthesis and evaluation”, Bioorganic and Medicinal Chemistry Letters, 2013, 23, 5119-5122.
Brown, D. P., Wong, T.; “A Synthetic Study of Dibenzo-Aromatic Macrolactams”, Heterocycles, 2010, 81, 149 – 161.
Brown, D. P., Duong, H. Q.; “Synthesis of Novel Aromatic Macrolactones via Ring Closing Metathesis of Substituted Phenylalkanoic Acid Allylic Esters”, J. Heterocyclic Chem.2008, 45, 435 - 443.
Brown, D. P., Krishnamurthy, L.; “Synthesis of New Medium Ring Aromatic Lactones via Halocyclization of 2-Hydroxyphenylalkanoic Acid Allylic Esters”, Heterocycles, 2004, 63, 1185 - 1192.
Brown, D. P., Durutlic, H., Juste, D.; “Spectroscopic Properties of Some Simple Esters – A practical Application of Synthesis and Spectroscopy in the Undergraduate Organic Laboratory”, J. Chem. Educ., 2004, 81, 1016-1017.
Brown, D. P., Griffith, E., Krishnamurthy, L.; “Novel Aromatic Lactones from Dihydrocoumarin through Electrophilic Heteroatom Cyclization”, J. Undergrad. Chem. Res., 2003, 3, 121-125.
Brown, D. P., Chen, W.; “1,1-Diphenyl-2-(trimethylsilyl)oxirane – Its Direct Conversion to the Allylsilane 1,1-Diphenyl-3-(trimethylsilyl)propene”, J. Undergrad. Chem. Res., 2003, 1, 11-13.
Brown, D. P., Box, V. G. S.; “The Synthesis of Chiral Allylsilanes, Spiroketals, and Dioxaspiro-compounds”, Heterocycles, 1991, 32, 1273.
CHE 1120 (Introduction to General & Organic Chemistry II)
CHE 1130 (Introduction to General & Organic Chemistry III)
CHE 2230 (Organic Chemistry I)
CHE 2240 (Organic Chemistry II)
CHE 2630 (Comprehensive Organic Chemistry I)
CHE 2640 (Comprehensive Organic Chemistry II)
CHE 3260 (Advanced Organic Chemistry – Undergraduate)
CHE 121 (Advanced Organic Chemistry – Graduate)
CHE 238 (Advanced Organic Synthesis – Graduate)
E. Emmett Reid Award in Chemistry Teaching for the mid-Atlantic region, American Chemical Society, May 2014.
Faculty Recognition Award, St. John’s College; 2014, 2013, 2008, 2006, and 2003.
Dr. John W. Dobbins Professor of the Year, St. John’s College, 2011 – 2012, Student Government Inc.
Professor of the Year, St. John’s College, 2005 – 2006, Student Government Inc.
Nominated for the Excellence in Teaching and Scholarship Award, St. John's University, January 2004.
Commitment and Service Award – Recognizing outstanding contributions to American Chemical Society Project SEED Program, September 2003.
Marshak Scholar, 1988 – Recipient of the Robert E. Marshak Distinguished Graduate Fellowship, The City College of New York.
Recipient of the Rockefeller Foundation Fellowship, 1986 – Bridge to Graduate Studies in the Sciences, The City College of New York.
St. John’s University, Office of Grants and Sponsored Research, 2013.
Summer Research Award, Bristol-Myers Squibb Pharmaceutical Company, Princeton, New Jersey, 2007.
Project Title: Synthesis of Natural Product Hybrids as New Antitumor Agents
Summer Research Award, Bristol-Myers Squibb Pharmaceutical Company, Princeton, New Jersey, 2006.
Project Title: Synthesis of Natural Product Hybrids as New Antitumor Agents
St. John's University Seed Grant / Venture Capital Grant, June 2003.
Project Title: The Stereoselective Synthesis of Pharmaceutical Intermediates via Heteroatom Cyclization Reactions.
St. John's University Summer Support of Research Program, Summer 2001
Project Title: The Development of New Antibiotic Antineoplastic Agents.
St. John's University Seed Grant / Venture Capital Grant, June 2000.
Project Title: The Design, Synthesis and Characterization of New Anthracycline Analogs as Potential Topoisomerase II Inhibitors.
American Chemical Society Project SEED, Summer II program, 2004, 2003.
American Chemical Society Project SEED, Summer I program, 2002.
The American Chemical Society and the New York Local Section, Active Member
1986 - 1994, Division of Organic Chemistry
1998 - Present, Division of Medicinal Chemistry
Site Coordinator & Mentor – American Chemical Society, Project SEED, 2003 – 2005.
Mission: To assure that students from economically disadvantaged backgrounds have opportunities to experience the challenges and rewards of chemically-related sciences.
Initiative for Minority Student Development Program (IMSD), Mentor, 2000 - 2003
Organic Chemistry Consultant, American Institutes for Research (AIR), Washington, D.C., 1994 – 1997.
Organic Chemistry Consultant, American College Testing Program (ACT), Iowa City, Iowa, 1990 – 1994.
The Association of American Medical Colleges (AAMC), 1990 – 1997.
Review Panel Service – National Project towards Building World Class Universities (WCU), Stanford Research Institute Inc., in collaboration with Korean Ministry of Education Science and Technology (MEST). This program, which provides funding for collaborative research projects in Korean universities, is part of a broader effort by the Republic of Korea to increase its investment in research and development, and expand international collaboration in science and technology. Reviews are presented orally at the WCU panel meeting in Arlington, VA.
Review Panel Service – National Science Foundation (NSF) Major Research Instrumentation (MRI). MRI proposals from both Ph.D. and non-Ph.D. granting institutions reviewed. Reviews presented at the NSF panel meeting in Arlington, VA.
PSC Review Service – Professional Staff Congress, CUNY, Recommendations provided on proposals submitted for funding consideration.
Manuscript Review – Ad hoc reviewer of research articles submitted for publication consideration in the Journal of Organic Chemistry, American Chemical Society – Reviewed 2 to 3 full length articles per year since 2004.
Ad hoc reviewer of leading educational titles in organic chemistry published by Wiley, Pearson, and McGraw Hill.