San Diego State University

Chemistry and Biochemistry



 

faculty photo

Shelli R. McAlpine, Ph.D.

Associate Professor
Medicinal Chemistry and Organic synthesis of natural products

Office: CSL 208
Office Phone: 619-594-5580
e-mail: mcalpine_at_sciences.sdsu.edu

Curriculum Vita

  • 1987-1991 B.S. U of Illinois Champaign/Urbana. Research with Prof Eric N. Jacobsen
  • 1991-1993 Research Associate Merck Pharmaceuticals
  • 1993-1997 Ph.D. UCLA Organic chemistry
  • 1997-2000 Post-doc at Harvard University with Professor Stuart Schreiber
  • 2000-2006 Assistant Professor at San Diego State University
  • 2006- Current Associate Professor at San Diego State University

McAlpine Group Page   |   McAlpine Research Projects


Research Interests

We are currently working on four organic synthesis projects and three biology projects. We are currently funded by three large grants for several of our projects: two are from NIH and the third is from the Frasch Foundation totaling ~ $2,057,500.   We have also received support from several other agencies including CSUPERB, the Howell foundation, and Pfizer, to name a few.  Thus, we are actively recruiting students.  We are looking for both synthetic chemists and biology students to do research in our group.  The synthesis in our group varies from making peptidomimetics using click chemistry to utilizing the Hantsch reaction and DAST dehydrations for the synthesis of complex natural products. Once synthesized, our group members run our compounds in biological assays ranging from basic cytotoxicity assays using up to 18 cancer cell lines (including colon, pancreatic, lung, breast, and prostate), to mechanistic assays involving apoptosis, pull-down, RNAi, and protein binding assays.  Thus, our group offers students the unique opportunity to do synthetic chemistry, biochemistry, and/or biology.  In addition, we have initiated computational docking studies, thus, students may also participate in molecular modeling.

 

Our organic chemistry projects focus on synthesizing derivatives of macrocyclic natural products, which make excellent synthetic starting points for developing new drugs.  By making derivatives, we establish structure-activity relationships (SAR) between the molecules and their biological target. These natural products are viable drug candidates, and their potency in numerous therapeutic areas has long been established.  There are currently 720 peptides that are drugs on the market or in some stage of clinical trials, and they are successfully used in the therapeutic areas of antibiotics, immunosuppressants, and as anticancer agents.  Shown below are the structures of the natural products that are being used as templates for derivatives made in our lab.  One of the compounds, Sansalvamide A (San A) was recently shown by our group to inhibit a very important cancer regulating protein: Hsp90. Hsp90 is a heat shock protein that regulates a number of oncogenic (growth inducing) client proteins.  Thus, by targeting Hsp90, San A and derivatives inhibit these client proteins from binding, which leads to their degradation, and ultimately causing the cell to die.  Thus, our San A derivatives are excellent potential anti-cancer agents, as they induce cell death at least through this mechanism, and perhaps others.  We are currently exploring San A’s mechanism of action and the Hsp90 client proteins affected by San A’s binding, as well as initiating mice toxicity studies.  We are also utilizing Autodock to determine the specific interactions that Hsp90 makes with the San A structure, thus allowing us to design additional new potent molecules.  Finally, we are making peptidomimetics in order to explore additional related structures that may have improved potency and stability in vivo.   In addition to the San A project, we are taking the same medicinal chemistry approach to the other structures, where we synthesize derivatives, run cytotoxicity assays to assess their toxicity, run pull-down assays to find the proteins that interact with these molecules in the cells, and run biochemical binding assays and western blots to evaluate their specific effects on these proteins.  

 

 

 

McAlpine structures

 

Since January 2006 we have published thirteen papers on three synthetic projects, and have two more papers submitted for publication (July 2009).  We have published 25 papers since my lab started at SDSU in 2001, and we currently have four patent applications.  We have presented our work extensively in the community. I have given 47 invited seminars since starting at SDSU and my students have presented 64 posters at meetings around the world (including presentations in Australia, England, ShangHai, and at Gordon conferences)! I expect my students to present at least once at a national or international meeting and to publish an average of three papers while in my laboratory.

 

Being an associate, tenured professor, I have established a full-fledged research program in organic synthesis, and have initiated biological assays on the compounds we synthesize.  Via my developed research program we plan to maintain publishing with the same frequency as we have accomplished in the past and I work with my students so that they typically publish on average one paper/year that they are in my lab.  Thus, I feel the community knows our work, which helps my students find jobs, enter graduate programs, and find post-doc positions.  Among my most recent students to graduate, one student has twelve publications, another has seven publications, while eight others have graduated with between 2 and 5 publications.  My masters’ students typically graduate with a minimum of two papers but often three, and I expect PhD students to graduate with a minimum of five papers (the most recent PhD to graduate has 12 publications to date).  Thus, we are a relatively productive group.  In addition, we raise money (~$3,500,000 to date) to fund our research (a total of 109 fellowships) and travel to meetings.  We currently have funding from or have been funded in the last year by: NIH (2 R01 grants and an R03), Frasch Foundation, CSUPERB, Pfizer, MIRT, and the Howell Foundation.  We have close ties to a number of local biotechnology companies, including Johnson and Johnson, Neurocrine, Celgene, Vertex, Illumina, and Ligand.  My students have been very successful in obtaining positions in a multitude of places including: Ph.D. programs in organic chemistry at UCI, UCSB, UPenn, Scripps, and the prestigious Ph.D. program at NIH-oxford university (accepts 6 student out of ~1000 applicants).  In addition, my students obtain excellent Post-doctoral opportunities with the most recent being with Prof. Gary Molander at UPenn. Finally, students choosing to go into industry have successfully obtained jobs after their degrees as organic chemists at local biotech companies including: Pfizer, Johnson and Johnson, Merck, Neurocrine, Ligand, Ambit, and the Burnham institute.  Because we have a diverse research program that ranges from synthesizing compounds to running biological assays, we encourage all students with interests ranging from organic synthesis to biology to explore the diversity of our projects and recognize the skills you will develop in our research group.  Thus, we are interested in recruiting both synthetically oriented students as well as biology students.  Please contact me if you are interested in learning more about our work. 

 

 

 

PUBLICATIONS

27)  Leslie  D. Alexander, Robert P. Sellers, Melinda R. Davis, Victoria A. Johnson, Veronica C. Ardi, and Shelli R. McAlpine* A potent new class of Hsp90 inhibitors: Di-sansalvamide A derivatives, submitted, 2009

26)  Robert C. Vasko, Rodrigo A. Rodriguez, Christian Cunningham, Veronica C. Ardi, David A. Agard, and Shelli R. McAlpine* Mechanistc studies of Sansalvamide A-amide: A potential allosteric modulator of Hsp90, Re-revision to J. Am. Chem. Soc. 2009

25)  Po-Shen Pan, Robert Vasko, Stephanie Lapera, Victoria A. Johnson, Robert P. Sellers, Chun-Chieh Lin, Chung-Mao Pan, Melinda R. Davis, Veronica C. Ardi, and Shelli R. McAlpine* A comprehensive study of Sansalvamide A derivatives: the structure-activity relationships of 78 derivatives in two pancreatic cancer cell lines, Bio. Org. Med. Chem. in press, 2009

24)  Rodrigo Rodriguez, Chung-Mao Pan, William Disman, Po-Shen Pan, Robert Vasko, and Shelli R. McAlpine* Structure-activity of Sansalvamide A derivatives and their mechanism of action in pancreatic cancer cell line PL45, J. Mex. Chem., v52, p201-211, 2008

23)  Erinprit K. Singh, Robert P. Sellers, Leslie D. Alexander and Shelli R. McAlpine* Conformational based design of macrocycles as antitumor agents. Current Opinion in Drug Discovery v11, p544-552, 2008

22)  Erinprit K. Singh, Suchitra Ravula, Chung-Mao Pan, Po-Shen Pan, Robert C. Vasko, Stephanie Lapera, Sujith, Mary Kay Pflum and Shelli R. McAlpine* Synthesis and biological evaluation of Histone Deactylase inhibitors that are based on the FR235222 scaffold, Bio. Org. Med. Chem. Lett, v18, p2549-2554,  2008

21)  Melinda R. Davis, Thomas J. Styers, Rodrigo A. Rodriguez, Po-Shen Pan, Robert C. Vasko, and Shelli R. McAlpine* Synthesis and cytotoxicity of a new class of potent decapeptides macrocycles, Org Lett.v10, p177-180 2008 (accepted 2007)

20)  Katerina Otrubova, Gerald H. Lushington, David Vander Velde, Kathleen L. McGuire, and Shelli R. McAlpine* A comprehensive study of Sansalvamide A derivatives and their structure-activity relationships against drug-resistant colon cancer cell lines, J. Med Chem, v51, p530-544 2008 (accepted 2007)

19)  Po-Shen Pan, Kathleen L. McGuire, and Shelli R. McAlpine* Identification of compounds potent against pancreatic cancer cell lines, Bio. Org. Med. Chem. Lett. v17, p5072, 2007

18)  Katerina Otrubova, Kathleen L. McGuire and Shelli R. McAlpine* A scaffold targeting drug-resistant colon cancers, J. Med Chem, v50, p1999-2002 2007

17)  Rodrigo Rodriguez, Po-Shen Pan, Chung-Mao Pan, Suchitra Ravula, Stephanie Lapera, Erin Singh, Thomas J. Styers, Joseph D. Brown, Julia Cajica, Emily Parry, Katerina Otrubova, and Shelli R. McAlpine* Synthesis of second generation Sansalvamide A derivatives: Novel Templates as Potent Anti-tumor Agents, J. Org. Chem. v72, p1980-2002 2007

16)  Thomas J. Styers, Ahmet Kekec, Rodrigo Rodriguez, Joseph D. Brown, Julia Cajica, Chris L. Carroll, Po-Shen Pan,  Irene Medina, Ricardo Corral, Jennifer V. C. Johnston, Emily Parry, Stephanie Lapera, Katerina Otrubova, Kathleen L. McGuire,*  and Shelli R. McAlpine* Synthesis of Sansalvamide A derivatives and their cytotoxicity in colon cancer cell line HT-29 Bioorganic and Medicinal Chemistry,  v14, p5625-5631 , 2006

15)  Po-Shen Pan, Fiona A. Curtis, Chris L. Carroll, Irene Medina, Lisa A. Liotta, Gary J. Sharples, and Shelli R. McAlpine*, “Novel Antibiotics: C-2 symmetrical macrocycles affecting Holliday Junction DNA processing” Bioorganic and Medicinal Chemistry,v14, p4731-4739, 2006

14)  Katerina Otrubova, Thomas J. Styers, Po-Shen Pan, Rodrigo Rodriguez, Kathleen L. McGuire,* and Shelli R. McAlpine*, “Synthesis and novel structure-activity relationships of potent  Sansalvamide A derivativesChemical Communications p1033-1034, 2006

13)  Thomas J. Styers, Rodrigo Rodriguez, Po-Shen Pan, and Shelli R. McAlpine*, “Synthesis of novel Sansalvamide A Derivatives via new, high yielding macrocyclization conditions”  Tetrahedron Letters, v47, p515-517, 2006

 


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