Chemistry and Biochemistry
McAlpine Group
Current Projects
We have chosen a number of different targets, and have published on four of these: Class B Synergimycin derivatives (antibiotic), C-2 symmetrical macrocyclic peptides that target Holliday Junctions (potential antibiotics), macrocyclic peptide derivatives of Sansalvamide A (potential antitumor agents), and a new class of compounds that are decapeptides (shows low nanomolar potency against pancreatic cancer cells). These macrocycles are used as probes to examine the binding sites of biological targets: the Ribosome with Class B Synergimycins, the Holliday Junction via our C-2 symmetrical hexa- and octa-peptide macrocycles, and Hsp90 for our Sansalvamide A derivatives (San A). Indeed, it was through our work on the San A’s that we determined they bind to Hsp90, a known oncogenic target.
Our current projects include the synthesis anti-tumor agents: Sansalvamide A derivatives, C-2 symmetrical decapeptides, Histone Deacetylase inhibitors, and Triostin derivatives, and the synthesis of antibiotics: C-2 symmetrical hexa and octa-peptides. All of these compounds are assayed by students in our lab, sometimes in collaboration with other faculty. In addition to running cytotoxicity assays on up to 18 different cancer cell lines, students in my lab also run a number of other biochemical assays examining the mechanism of action for specific macrocycles. These assays include apoptosis, pull-down, RNAi, and western blot assays. Thus, our group offers the unique opportunity to do synthetic chemistry, biology, or both.
The first project involves the synthesis of Sansalvamide A (San A) derivatives, where ∼100 derivatives have been made to date. We tested these analogs against a number of drug-resistant colon cancer, pancreatic, prostate, and lung cancer cell lines and found that ∼10 compounds exhibit potent cytotoxicity against these cancer cell lines. One compound exhibited potency comparable to a current drug on the market in drug-resistant colon cancer cell lines, and another exhibited activity against pancreatic cancer cell lines comparable to drugs treating other cancers (currently there are essentially no chemotherapeutic options for pancreatic cancers). In addition we are running a series of biochemical assays to explore the mechanism of action of these potent San A derivatives. These include: pull-down assays, where students in our lab have determined that Hsp90 is the primary target for these San A derivatives. Further, we have shown that these compounds exhibit apoptosis in several cell lines. In addition, in collaboration with our colleagues at Johns Hopkins (the Snyder lab) we have demonstrated that they inhibit Hsp90 via a unique mechanism at the C-terminal binding site of Hsp90. Given that Hsp90 is a protein that is typically upregulated in most cancer cells it is an ideal target. Further, there is currently a drug in clinical trials that binds to the N-terminal binding site of Hsp90, but there are no compounds in clinical trails that target the C-terminal binding site. Thus, we have an opportunity to develop a novel compound with a unique mechanism of action. In collaboration with the Snyder lab and the Moffit institute we have RNAi data and western blot data on these compounds, and are now learning a number of other biochemical techniques that will explore these compounds therapeutic potential as anti-cancer agents in mice.
Our second synthetic project involves the synthesis of C-2 symmetrical decapeptides that have shown to be extremely potent against pancreatic and drug-resistant colon cancer cell lines. These compounds are more potent than any drug to date against these cancer cell lines (sub nanomolar). We are currently synthesizing compounds to be utilized in pull-down assays, whereupon we will complete a series of biochemical and biological assays to evaluate what target is being hit by these compounds. This exciting new series of compounds is first in class, and has extraordinary potential as a potent anti-cancer agent as it exhibits 5-15 nM potency against all cancer cell lines tested to date, and shows ~30 fold differential selectivity between normal cell lines versus cancer cell lines, indicating it is not uniformly toxic. Further assays will confirm that it is indeed a new lead to a class of structurally unique compounds. Our third project involves the synthesis of macrocycles that inhibit Histone deactylases (HDACs). HDACs are a promising new target for shutting down cell growth of certain cancers. We recently started this project and have completed 6 novel compounds, where 2 compounds inhibited deacetylase activity. We are now synthesizing additional analogs to include peptidomimetics using click chemistry. Our fourth project involves the synthesis of Triostin derivatives. These compounds are known potent antitumor reagents, and we anticipate they will be run in the same biological assays described for the San A analogs. These compounds demonstrate a great deal of potential as anti-cancer agents, and we have optimized the synthesis needed to rapidly and succinctly complete a series of Triostin derivatives. Finally, our fifth project involves the synthesis and evaluation of novel C-2 symmetrical macrocycles as antibiotics. We are currently testing a series of compounds against gram-ve and gram+ve strains of bacteria, and have found a 1µM inhibitor to date. Given that the drug of last resort, Vancomycin, typically kills these strains at ≥8µm, these compounds exhibit exciting potential as a new class of antibiotics. The mechanism of action for these compounds is under investigation.