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The CPRIT lab is a collaboration center with synthetic organic/medicinal chemistry expertise serving as an interface between bioactive small molecule/natural product identification and cell biology/mode of action studies for drug discovery. We would be interested in future collaborations, including grant proposals, if you need synthetic organic chemistry or reaction screening and optimization support for one of your projects. Please contact us:
Phone: (254) 710-2162
CURRENT COLLABORATORS | PAST COLLABORATORS:
Johns Hopkins University (Medicine)
“Syntheses of Lactimidomycin Analogues”
It was reported that lactimidomycin (LTM), is not only a cell migration inhibitor, but also has a potent antiproliferative effect on tumor cell lines (such as HeLa, MDA-MB231 and Jurkat T cells) with IC50 in the nanomolar range and selectively inhibit translation. A systematic comparative study of the effects of LTM on protein synthesis directed by Dr. Liu revealed that LTM blocks the translocation step in elongation by binding to the 60S ribosome, suggesting that inhibitors of eukaryotic translation elongation may have the potential of becoming new anticancer agents. We are developing synthetic routes for making a small collection of greatly simplified lactimidomycin analogues. The goal of this collaboration is to perform a more complete structure activity relation (SAR) study on LTM than has been done previously, to further enhance the potency and specificity of LTM through chemical modification of LTM structure and develop more potent, yet simplified lactimidomycin analogs, which could potentially become anti-cancer drug candicates.
“Derivatization of Triptolide”
Triptolide is a structurally unique diterpene triepoxide isolated from the Chinese plant Tripterygium wilfordii, with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Triptolide shows strong antiproliferative activity against all 60 US NCI cancer cell lines with IC50’s in the low nanomolar range. Prof. Liu recently reported that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely to inhibition of nucleotide excision repair. However, the effect of triptolide on polycystin-2 remains a mystery. The goal of this collaboration is to: 1) synthesize triptoide probes useful for identification of the other protein targets of triptolide and further understand the interaction between triptolide and its targets for mode of action study; 2) synthesize triptolide derivatives for SAR studies and 3) develop new triptolide analogs with enhanced antitumor potency and reduced toxicity through chemical modification of triptolide structure.
Jun Liu and Dr. Armen Zakarian
“Derivatizatin of trichodermamide B for SAR study and MOA studies”
Trichodermamide B was isolated as the secondary metabolites from marin-derived fungal strains. It shows significant in vitro cytotoxicity against several cancer cell lines (e.g. HCT-116 human colon carcinoma with an IC50 = 710nM, HeLa cells with an IC50 = 40nM) and moderate antimicrobial activity against certain drug-resistant bacterial strains. So far, little progress has been made on the SAR study of this attractive molecule and its biochemical target and mechanism of action remain unknown. Our goal is to make trichodermamide B derivatives for SAR studies, to make probes for target identification and MOA studies, and eventually to apply this knowledge to the design of new trichodermamide B based anti-cancer agents.
Jun Liu and Dr. Ali Al Mourabit
“Derivatizatin of Girolline for SAR study and MOA studies”
Girolline (RP 49532A) is a protein-synthesis inhibitor isolated from a marine sponge that exhibits significant cytotoxicity in vitro against several cancer cell lines and antitumor activity in vivo against murine grafted tumors including P388, L1210 leukemias, and solid tumors. Studies indicated that girolline binds near the E site region of the 50S ribosomal subunit of haloarcula marismortui and likely inhibit tRNA binding by interfering with conformational changes that occur at the E site of the 50S ribosome. In addition, girolline also exhibits strong antimalarial activity against four Plasmodium falciparum strains with IC50‘s ranging from 77 to 215 nM. The investigation into the mechanism of action of girolline during the erythrocytic life cycle of the parasite suggested that its action targets the synthesis of proteins by the parasite. Such biological profile of girolline makes it a model chemical structure for new candidates in the arsenal of new drugs against cancer and malaria. Our contribution to this collaboration is to make radiolabeled girolline to further understand the interaction of girolline with its biochemical target, and to make new girolline analogs for SAR studies and structural modification heading to the new drug lead discovery.
Benjamin Cravatt and Dr. Abimael Rodriguez
“Derivatization of Marine Sponge Derived Natural Products.”
Natural products from marine sources are a rich source of anti-cancer agents. Dr. Rodriguez had recently isolated, from marine sponges around Puerto Rico and its neighboring islands, several gorgonian cembranoids (such as eupalmerin acetate (EPA), iso-EPA and eupamerolide) with nanomolar to low micromolar activities against several cancer cell lines (e.g. leukemia, breast cancer, non-small cell lung cancer, colon cancer, prostate cancer etc.). The purpose of this collaboration is to make derivatives and probes of eupalmerins for subsequent activity based profiling experiments in order to further understand the molecular mechanism of action of these compounds, and to explore the potential for development of these potent natural products into anticancer agents.
“Comparative Mechanisms of Cancer Prevention”
The genesis of this project dates back 30 years to a program focused on the anticancer mechanisms of indole-3-carbinol (I3C), 3,3’-diindoylmethane (DIM) and related dietary indoles. A programmatic shift occurred when the research team discovered the histone deacetylate (HDAC) inhibitory actions of another compound from cruciferous vegetables, namely sulforaphane (SFN), which put the work at the interface of epigenomics, diet, and cancer prevention. One of the fundamental principles governing this research is that, unlike the genetic changes in cancer that are essentially irreversible, epigenetic mechanisms are potentially modifiable by our diet and lifestyle. Based on mechanistic studies in cell-based assays, experiments in preclinical models, and data from human trials, the research moved into new directions focused on the role of epigenetic readers/writers/erasers and the expression and processing of RNAs. The CPRIT lab will use our toolkit of reactions to prepare biotin tagged derivatives of metabolites of sulforaphane (SFN) and indole-3-carbinol (I3C) that were previously and continue to be identified. Additionally, if the bioactive metabolite is not commercially available, the CPRIT Lab will develop a synthetic process to prepare metabolites.
“Fatty acid synthase and proteasome inhibitor-loaded nanocages to treat osteosarcoma lung metatases”
This collaboration brings together newly discovered dual inhibitors of two anticancer drug targets, fatty acid synthase (FAS) and the proteasome, together with hollowed-out nanoparticles (nanocages), and cell biology and membrane transport studies to form a high-impact technology for the treatment of osteosarcoma lung metastases. The goal of the project is to demonstrate the protection of potentially sensitive inhibitors and their targeted delivery to tumor sites in the lung. We are contributing to this collaboration by designing and synthesizing novel dual analogs of FAS and the proteasome based on the natural product belactosin C.
“Inhibition of protein translation as a molecular target for longetivity enhancement.”
Multiple genome-wide studies in Saccharomyces cerevisiae and Caenorhabditis elegans have found knockouts or knockdowns of the eularyotic initiation factor-4A (eIF4A) to cause significant increases in lifespan. Our collaborator has recently identified the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We are collaborating with Dr. Huang by supplying sample of the potent, selective translation inhibitor DMDAPatA for her further studies to understand the linkage between inhibition of translation initiation and longevity enhancement.
“Derivatization of the anticancer taccalonolide A and B toward the discovery of new microtubule stabilizers with clinical potential”
The tacalonolides are a novel class of microtubule stabilizing agents isolated from the tropical plant Tacca chantrieri. This family of compounds exhibits nanomolar activities against several cancer cell lines (such as SK-OV-3, HeLa, wildtype bIII etc.). Their unique structure and inability to directly bind to or stabilize tubulin in vitro strongly suggest that the taccalonolides cause microtubule stabilization through a distinct mechanism of action. Recent research in Dr. Mooberry’s lab has demonstrated that the taccalonolides have advantages over the taxanes in clinically relevant drug resistant cell lines and tumor models. Therefore, the taccalonolides represent a novel family of microtubule stabilizing agents with clinical potential. The goal of this collaboration are: 1) to synthesize taccalonolide probes in order to identify their protein targets and binding site; 2) to further understand the interaction between the taccalonolides and their biochemical targets in order to reveal their molecular action mechanism as microtubule stabilizer; 3) to synthesize taccalonolide derivatives for SAR studies; 4) to further increase the antitumor potency of the taccalonides through chemical modification.
Sergio Serna Saldivar
“Discovery of bioactive natural products from indigenous Mexican plants as potential anti-cancer drug candidates”
Mexican has some of the greatest flora biodiversity in the world. Many indigenous plants from Mexico have been well known and utilized in folklore medicine for both treatment and prevention of various diseases such as cancer, diabetes, and bacterial infection. Importantly, many of these plants have not yet been studied and thus represent a large potential pool of bioactive natural products with untapped therapeutic potential. The purpose of this collaboration is: 1) The isolation and identification of novel anticancer agents from plant sources; 2) Structural modifications of the warrant natural products for SAR studies; 3) Probe synthesis for target identification and MOA studies. We hope to advance a natural product with interesting bioactivity to the point at which it can be considered to be a clinical candidate.
“Isolation and structure elucidation of anticancer agents from the Colombian plant Petiveria alliacea”
It was found that the extract from Petiveria alliacea exerts multiple biological activities in vitro consistent with cytotoxicity. For example, it can alter actin cytoskeleton organization, induce G2 cell cycle arrest and cause apoptotic cell death in a mitochondria independent way. Such a profile indicates that Petiveria alliacea extract may be a very important source of antitumor agents. This collaboration focuses on the isolation and identification of anticancer agents from Petiveria alliacea extract. Further structural modification and probe synthesis will also be performed if any novel bioactive natural products are isolated from Petiveria alliacea extract.
DMDAPat A: a potential cancer drug lead
DMDAPatA, a simplified analog of the marine natural product Pateamine A, is an antiproliferative and anti-inflammatory agent discovered jointly and patented by Texas A&M University and the Johns Hopkins University. DMDAPatA inhibits translation initiation by binding to the ATP-dependent helicase, eIF4A, promoting formation of a stable ternary complex between eIF4A and eIF4B and thus preventing formation of the required eIF4G initiation complex and causing apoptosis. At concentrations less than 100 nM, DMDAPatA inhibits proliferation of a diverse array of human cancer cell lines and exhibits selectivity (~1,000-fold) between proliferating and quiescent cells. For example, DMDAPatA has potent antitumor activity against LOX melanoma xenografts and MDA-MB-435 melanoma xenografts in mice at 0.7 mg/kg and 0.94 mg/kg, respectively. We have a number of collaborations involving DMDAPatA underway for the purpose of gaining more evidence of its usefulness against various cancers and investigating what other roles a translation inhibitor might have in medicine.
“Study and development of protein translation inhibitors for the treatment of advanced breast cancers”
Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer. The unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumor cell survival and formation of tumor emboli. Overexpression of eIF4GI promotes formation of IBC tumor emboli by enhancing translation of IRES-containing p120 mRNAs. Dr. Schneider is investigating inhibitors of translation initiation in animal models of advanced breast cancers. We are providing sample of the novel protein translation inhibitor DMDAPatA for use in in vivo studies.
Vitaly Polunovsky, Dr. Peter Bitterman, Dr. Carston Wagner, and others
“Targeting Oncogenic eIF4F-Mediated Protein Synthesis for Therapy of Epithelial Carcinomas”
We are working within a NIH multicenter project, which aims to systematically deconstruct the neoplastic phenotype in common epithelial cancers – breast, ovarian and lung – using small molecule inhibitors of deregulated translational machinery. The goal of the proposed research is to develop a better understanding of the role of translational control on cancer and angiogenesis. To this end, chemical biological probes have an important function in delineating the role of key pathways on the biological and physiological function of the components of eIF4F. In addition, these chemical probes serve as useful drug discovery lead compounds. We will support this project by providing samples of our protein translation inhibitor DMDAPatA as well as designing and synthesizing biochemical probes useful for studying the mechanism and effects of inhibition of the protein translation machinery.
“Derivatization of pyrazinamide and ethambutol in search for new generation drugs against tuberculosis”
Tuberculosis (TB) is a disease of antiquity which is thought to have evolved sometime between the seventh and sixth millennia BC. Current estimates suggest that one third of the world’s population is infected, resulting in some 2 million deaths per year, of which 450,000 are children. Concomitant with the resurgence of TB has been the occurrence of multidrug-resistant disease, which has exposed the frailties of the current drug armamentarium. There is now recognition that new drugs to treat TB are urgently required, specifically for use in shorter treatment regimens than are possible with the current agents and which can be employed to treat multidrug-resistant and latent disease. Ethambutol is one of the main drugs used in TB-treatment regimens and in most countries it has now replaced streptomycin and thiacetazone. Although it is believed that ethambutol interferes with construction of the arabinogalactan layer of the mycobacterial cell wall, its mode of action is not known with certainty. Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis. Its active form, pyrazinoic acid, which accumulates in the bacilli, is believed to inhibit the enzyme fatty acid synthase (FAS). It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production necessary for survival of M. tuberculosis at an acidic site of infection. However, these suggestions are still under debate. The goals of this collaboration include: 1) to make probes of these two molecules in order to identify their targets and clarify their respective modes of action; 2) to make ethambutol and pyrazinamide derivatives as potential new drug leads for the treatment of multidrug-resistant and latent TB.
“Derivatization of tetrahydrolipstatin for drug development against M. tuberculosis”
Though M. tuberculosis is one of the oldest known human pathogens, our ability to combat spread of this disease remains insufficient, and the global health burden of tuberculosis is increasing. Mycobacteria are uniquely rich in unusual fatty acids and lipids. The goal of this collaboration is to explore the known inhibitor of pancreatic lipase tetrahydrolipstatin (orlistat) as a lead compound for drug development against M. tuberculosis, using one of its known targets, the essential enzyme Rv3802, and any alternative targets that may be identified, for optimization.
Preeeclampsia and traumatic brain injury:
Jules Puschett and Dr. Luc Berghman
“Evaluation of the bufodienolides in the prediction and prevention of preeclampsia”
Preeclmpsia (PE) is a pregnancy-specific syndrome which is the second leading cause of maternal and fetal morbidity and mortality in the US, occurring in from 3-10% of pregnancies. There is currently no reliable predictor of its later development in pregnancy, nor is there adequate and safe drug treatment or prevention of this illness. Our ongoing collaboration has led to the discovery of a potential and predictive agent, as well as an antagonist to this agent, which can be used to prevent PE. The goal of the ongoing collaboration is to broaden these studies to investigate other possible predictive agents, which appear in the blood and urine; and to identify other antagonists to these agents, which can effectively prevent and/or treat PE. We are also planning to explore the utility of these techniques in treatment of brain trauma and volume expansion-mediated essential hypertension.
“Marinobufagenin Levels in Preeclamptic Patients: A Preliminary Report”, Horvat, D.; Harrison, R.; Uddin, M.N.; Jones, R.; Abi Ghanem, D.; Berghman, L.C.; Lai, X.Z.; Li, J.; Romo, D.; Puschett, J.B. Amer. J. Perinatology, 2011, Accepted.
“A Chemifluorescent Immunoassay for the Determination of Marinobufagenin in Body Fluids”, Abi-Ghanem, D.; Lai, X.Z.; Berghman, L.R.; Horvat, D.; Li, J.; Romo, D.; Uddin, M.N.; Kamano, Y .; Nogawa, T.; Xu, J.P.; Pettit, G.R.; Puschett, J.B. J. Immunoassay Immunochem, 2011 , 32, 31-46.
Dr. Raushel studies the fundamental principles involved in enzyme-catalyzed chemistry. The CPRIT lab has synthesized inhibitors and substrates of the enzymes of interest to Dr. Raushel’s group so they can study the mechanism and function of these interesting proteins.
Rajani Srinivasan and Dr. Alexzander Asea
“Characterization of plant-based delivery system”
In order to support drug delivery system development based on polysaccharides derived from plant sources for delivery of anticancer cells intravenously/subcutaneously, we performed characterization of the materials and material drug composites using various analytical techniques such as IR, NMR, MS, DSC, and TEM.