2004 — 2005 |
Andrade, Rodrigo B [⬀] |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Enantioselective Total Synthesis of (+)-Halichlorine @ University of Texas Austin
[unreadable] DESCRIPTION (provided by applicant): A strategy for the efficient, enantioselective synthesis of (+)-halichlorine, a marine natural product which inhibits VCAM-1 (vascular cell adhesion molecule-1) with an IC50 of 7 [unreadable]g/mL, is proposed. Due to its critical role in the regulation of inflammation, VCAM-1 has emerged as a potential target for drug discovery. Inhibitors of this protein could have a profound impact on the treatment of arteriosclerosis, asthma, and cancer. To date there only exists one total synthesis of halichlorine. The proposed plan outlines a novel synthetic route to halichlorine which can be modified to access precursors of pinnaic acid, a related alkaloid and potent inhibitor of cytosolic phospholipase A2. The plan utilizes cress-metathesis methodology for the construction of key olefinic bonds which heretofore has not been used in alkaloid synthesis. This represents a unique opportunity to study the scope of cross-metathesis in total synthesis. An intramolecular Kishi-Nozaki reaction is also proposed as an alternative macrocyclization step. Molecular modeling suggests the reaction will take place with a high degree of diastereoselectivity in favor of the desired stereoisomer. The synthesis will furnish sufficient quantities of halichlorine to assess its potential as a candidate for the treatment of the above conditions. [unreadable] [unreadable] [unreadable]
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0.961 |
2009 — 2012 |
Andrade, Rodrigo B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Discovery of Novel Macrolide Antibiotics @ Temple Univ of the Commonwealth
Project Summary The rapid and incessant rise in antibiotic-resistant bacteria represents a serious public health threat that must be addressed.1 Economic pressures have resulted in an overall decrease in the number of pharmaceutical companies with active antimicrobial research programs, underscoring the need for new sources of antibiotics.2 The broad, long-term goal of the proposed work is to meet this need by discovering novel macrolide antibiotics that directly address known resistance mechanisms by rational drug design. The mechanism of macrolide antibiotic drug action is known.3 These drugs bind the bacterial ribosome and prevent protein synthesis. Recently, crystal structures of various macrolide drugs (e.g., erythromycin, telithromycin, azithromycin) bound to ribosomal subunits have been solved, offering valuable structural insight as to how these compounds bind (i.e., contact with ribonucleotide residues) and how resistance mechanisms undermine drug action.4 Resistance mechanisms in which the ribosome itself is modified represent a formidable challenge to medicinal chemists.5 To address these particular mechanisms and facilitate chemical synthesis, the paradigm of natural product structure simplification (molecular editing)6 will be applied to the ketolide telithromycin, a 3rd generation semisynthetic drug derived from the flagship macrolide antibiotic erythromycin A and used in the clinic since 2004.7 Aims include (1) the application of computer-aided drug design (CADD) tools that will first evaluate a virtual library of selected macrolide analogues bound to both wild-type and resistant ribosomal subunits to determine the candidates most likely to have bioactivity and overcome resistance. In tandem, (2) chemical synthesis featuring novel methodology will provide access to material, which will (3) be screened against drug-susceptible and drug-resistant bacterial strains. This will serve to test the hypothesis that structural simplification of the complex macrolide architecture will directly address resistance without compromising bioactivity. Another round of CADD will serve to optimize the most promising candidates. Bioassays will measure success in this endeavor.
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0.928 |
2011 — 2017 |
Andrade, Rodrigo [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Asymmetric Synthesis of Strychnos and Aspidosperma Alkaloids
AWARD ABSTRACT
In this project funded by the Chemical Synthesis program of the Chemistry Division, Professor Rodrigo B. Andrade of Temple University (Department of Chemistry) is studying the development of new chemical reactions to quickly build complex nitrogen-containing molecules. An overarching goal is increasing the efficiency of making complex molecules having broad societal impact by minimizing the overall number of synthetic steps. An overwhelming number of such molecules are biologically active, and can be employed in molecular biology to understand biochemical pathways or directly applied in medicine to better understand disease on a molecular level. The chemical insight can then be applied in therapeutic regimes. To test the scope of these new methods, several complex molecules derived from nature are being prepared in the laboratory. During the development and application of these new methods, undergraduate and graduate students, including those from underrepresented groups, are being trained in the discipline of complex molecules synthesis.
This project systematically studies and applies a novel domino Michael/Mannich [4+2] annulation method to the synthesis of complex molecules. In Aim 1, the nucleophilic and electrophilic components of the method are being examined to determine the reaction scope. In Aim 2, the method is applied to the asymmetric total syntheses of the Aspidospermatan-type alkaloids (+)-epi-condyfoline, (+)-condyfoline, (+)-lagunamine, (+)-epi-lagunamine, (+)-condylocarpine, (+)-isocondylocarpine, and (+)-tubotaiwine. In Aim 3, the method is used to develop the asymmetric total syntheses of the bis-Aspidosperma alkaloids (-)-conophylline and (-)-conophyllidine.
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0.915 |
2017 — 2020 |
Andrade, Rodrigo [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Asymmetric Synthesis of Alkaloids Enabled by Novel Methodology
The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Rodrigo B. Andrade. Professor Andrade is a faculty member in the Department of Chemistry at Temple University. He is developing new chemical reactions to quickly build complex nitrogen-containing molecules. The overarching goal is to maximize the efficiency by which complex, three-dimensional molecules are prepared by using new reagents and reactions discovered in his laboratory. Such an approach reduces the time, energy, and cost associated with synthesizing complex molecules composed of carbon and nitrogen atoms. Many such molecules are biologically active, and so they can be employed as molecular probes to better understand biochemical pathways or as therapeutics to be used in medicine. Beyond the training of undergraduate and graduate students, including those from underrepresented groups, the broader impacts of this project touch the fields of organic chemistry (e.g., total synthesis, synthetic methodology), chemical biology, molecular biology, biochemistry, and medicine.
N-Sulfinyl metallodienamines (NSMDs) have emerged as powerful asymmetric synthons for chemical synthesis. The focus of this project is to determine both the mechanism and scope of reactions using acyclic NSMDs with a variety of electrophiles, which logically builds from previous efforts on arene-fused congeners. Specifically, in Aim 1 the researchers are studying the scope of the reactions of acyclic NSMDs with electrophilic olefins to afford cycloadducts through a Domino Michael/Mannich (formal Diels-Alder) process. In Aim 2, the research group is applying optimal reaction conditions determined from Aim 1 toward the step-efficient, asymmetric total syntheses of complex Iboga alkaloids (+)-catharanthine, (+)-coronaridine, and (+)-ibogamine. In Aim 3, the research students are systematically investigating the reactions of NSMDs with aldehydes (vinylogous aldol) and imines (vinylogous Mannich). In Aim 4, researchers are probing the reactions of NSMDs with electrophilic oxygen and nitrogen sources to access alpha-functionalized N-sulfinyl imines, which can be further modified to access chiral building blocks for organic synthesis. Computer modeling is used in all mechanistic analyses. Professor Andrade has demonstrated a strong commitment to the inclusion of undergraduates, particularly from underrepresented groups, in his research activities.
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0.915 |
2018 — 2019 |
Andrade, Rodrigo B |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synthesis and Evaluation of Narrow-Spectrum Antibiotics Targeting Mrsa @ Temple Univ of the Commonwealth
Project Summary/Abstract Natural products account for two-thirds of the antibacterial pharmacopeia and are therefore privileged scaffolds. These complex molecules have inspired novel synthetic methods and positively impacted the fields of biochemistry, molecular biology, and medicine. The proposed project is inspired by albocycline, a unique 14-membered macrolactone with potent, narrow-spectrum activity against the ?superbug? methicillin- resistant Staphylococcus aureus (MRSA). We have validated that albocycline is effective against MRSA and vancomycin-resistant S. aureus strains; moreover, it is non-toxic to human cells. In 2013, Tomoda reported that albocycline inhibited peptidoglycan (i.e., bacterial cell wall) synthesis in macromolecular assays. Using biochemical assays and molecular modeling, we demonstrated that albocycline was a weak (mM) inhibitor of MurA from S. aureus. Consistent with its narrow-spectrum profile, albocycline did not inhibit MurA from E. coli. Based on our results and those of Tomoda, we conclude it must have additional bacterial targets. Significantly, we recently completed a modular, step-efficient total synthesis of the natural product driven by novel chemistry of N-sulfinyl metallodienamines. Accordingly, in Aim 1 we propose to prepare albocycline analogs (including probes) by semi- and diverted total synthesis to explore the chemical space about this privileged scaffold. In Aim 2, we will co-crystallize albocycline in complex with MurA based on exciting preliminary results and employ structure-based analog design. We will also identify the target(s) of albocycline to determine its mode-of-action using computational chemistry, chemical proteomics and genomics approaches, in addition to a novel metabolic labeling methodology. Finally, in Aim 3 we will evaluate the biological activity of all albocycline analogs. At the end of the four-year project period, we will have (1) a deeper understanding of how albocycline exerts its antibacterial action; (2) a library of tool compounds and antibiotic lead candidates that selectively modulate their target(s); and most significantly, (3) a bona fide launching point for the development of novel, narrow-spectrum antibiotics to treat recalcitrant MRSA, VISA, and VRSA (i.e., the project's long-term goal).
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0.928 |
2020 — 2021 |
Andrade, Rodrigo B Ma, Grace X. Matsika, Spiridoula |
T34Activity Code Description: To enhance the undergraduate research training of individuals from groups underrepresented in biomedical, behavioral, clinical and social sciences through Institutional National Research Service Award Training Grants, in preparation for research doctorate degree programs. |
Marc At Temple University @ Temple Univ of the Commonwealth
Project Summary/Abstract MARC at Temple University Building on the 10-year success of ?TU MARC U* STAR Program,? Temple University (TU) seeks funding to advance its mission to train undergraduate students of racial/ethnic and disadvantaged groups that are traditionally underrepresented (UR) in biomedical sciences, and prepare them for graduate school PhD or MD/PhD programs. TU provides access to a relatively large undergraduate population of UR students consistently ranking in the top programs in the nation in undergraduate diversity. In the College of Science and Technology (CST), black and Hispanic students comprise 24% of the total. Many TU undergraduate students are first-generation college students and many UR students attended public schools in the Philadelphia area. Underprepared students have few college-level study skills, and often have part- or full-time jobs. TU has the potential to increase the pool of students who would not otherwise consider or be prepared for PhD programs. Our initial MARC program was established at Temple University in 2009 with funding for the first cohort of 8 rising juniors. We successfully oriented students to research and a built cohort, students were assigned to faculty mentors matched with their research interests. Mentors from TU included faculty in the College of Science and Technology, research centers at Lewis Katz School of Medicine (LKSOM), College of Engineering (Bioengineering Department) and College of Public Health. Over the past 10 years of two funding cycles (2009- 2019), our MARC program graduates successfully enrolled in or graduated from PhD, MD/PhD or enrolled in PREP programs for PhD or MD/PhD or Master?s program with goal of entering a PhD program. Our overall success rate of MARC graduates entering graduate programs in biomedical sciences within 3 years of graduation is 85%. In this application, we aim to extend and expand the MARC program by addressing the shortfall of college students in biomedical sciences and urgent need to increase the diversity of biomedical and behavioral research. We have and will continue to address the need to ensure more UR undergraduates pursue PhD or research-focused MD/PhD programs. The successful features of the past program will be integrated with new components with the addition of the community engagement in research training. The goal is to build on the research support at Temple University from the CST Research for Undergraduate Program (URP), LKSOM U54 Cancer Health Disparity Research and Education program (PI: Dr. Ma) and T32 programs, as well as continue student research support through graduation and transition into graduate PhD or MD/PhD programs. We will enroll 16 promising students into our MARC program for two years of research support. Faculty mentors across multi-disciplines and colleges agreed to provide full-time, hands-on research training and mentorship. Trainee measurable outcomes will be GPA, number of research presentations and co-authored publications and acceptance to competitive PhD or MD/PhD programs through graduation and participation in the biomedical workforce as a result of improved research, communication and social skills/emotional intelligence.
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0.928 |