We
are currently working on four organic synthesis projects and three biology
projects. We were recently awarded two large grants for several of our
projects: one from NIH and the other from the Frasch Foundation totaling ~ $1,300,000.
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 KAHA ligation chemistry and click chemistry
to the synthesis of complex natural products based on large macrocycles. The
compounds we make are run in biological assays by our group. The biology
experiments we run range from basic cytotoxicity assays on up to 18 cancer cell
lines (including colon, pancreatic, lung, breast, and prostate), to mechanistic
assays involving apoptosis, pull-down, RNAi, and western blots. Thus, our
group offers students the unique opportunity to do synthetic chemistry,
biology, or both.
Currently,
three of the four 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 (C & E news
March 14, 2005). 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, San A
was recently shown by our group to inhibit a very important cancer regulating
protein: Hsp90. This compound has demonstrated such tremendous potential that
we are now starting mice toxicity studies. We are also making peptidomimetics
of all four classes of compounds shown in order to explore additional related
structures that may have improved potency and stability in vivo.
Since
January 2006 we have published twelve papers on three synthetic projects, and
have two more papers submitted for publication (October 2008). We have
published 21 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 46 invited seminars since starting at SDSU and my
students have presented 63 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 one paper/year. 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
(~$2,200,000 to date) to fund our research (a total of 78 fellowships) and
travel to meetings. We currently have funding from or have been funded in the
last year by: NIH, 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, 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
25) Po-Shen Pan, Robert
Vasko, William Disman, Stephanie Lapera, Melinda Davis, and Shelli R. McAlpine*
A comprehensive study of Sansalvamide A derivatives: their
structure-activity relationships and their binding mode to Hsp90, submitted,
2008
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, in press,
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 derivatives” Chemical 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
12) Shelli R. McAlpine, Life
as an academic: being a female assistant professor in chemistry, American
Chemical Society book: Gladly We Teach, p59 August 2005
11) Chris L. Carroll,
Jennifer V. C. Johnston, Ahmet Kekec, Joseph D. Brown, Emily Parry, Julia
Cajica, Irene Medina, Kristina M. Cook, Ricardo Corrall, Po-Shen Pan, Ricardo
Corral, and Shelli R. McAlpine* “Synthesis and cytotoxicity of novel
Sansalvamide A derivatives” Organic Letters, v7, p3481-3484 2005
10) Lisa A. Liotta, Irene
Medina, Jennifer L. Robinson, Chris L. Carroll, Po-Shen Pan, Ricardo Corral,
Jennifer V. C. Johnston, Kristina M. Cook, Fiona A. Curtis, Gary J. Sharples,
and Shelli R. McAlpine* “Novel antibiotics: Second generation macrocyclic
peptides designed to trap Holliday Junctions” Tetrahedron Letters,
v45, p8447-8450 2004
