Md. Jashim Uddin, Ph.D.

Research Associate Professor

jashim.uddin@vanderbilt.edu

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Faculty Appointments
Research Associate Professor of Biochemistry
Education
Ph.D., Organic Chemistry, Shinshu University, Nagano, JapanM.S., Chemistry, University of Dhaka, Dhaka, BangladeshB.S., Chemistry, University of Dhaka, Dhaka, Bangladesh
Office Address
850 RRB,
Department of Biochemistry, Vanderbilt University School of Medicine
23rd at pearce
nashville, TN 37232-0146
Research Description
Cyclooxygenase-2 (COX-2) catalyzes the committed step in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. COX-2 is not expressed in most normal tissues but is present in inflammatory lesions and tumors. The expression of COX-2 appears to be an early event in tumorigenesis that plays a role in tumor progression. COX-2 mRNA and protein are detectable in a significant percentage of precursor lesions (e.g., colon polyps, Barrett’s esophagus) and an even higher percentage of malignant tumors (e.g., colon adenocarcinoma, esophageal adenocarcinoma). The other form of cyclooxygenase, COX-1, does not appear to be elevated in tumors with the exception of ovarian carcinomas. Thus, COX-2 may be responsible for the significant increase in prostaglandin biosynthesis observed in many human tumors. COX-2 is the molecular target for the anti-inflammatory, analgesic, and antipyretic effects of non-steroidal anti-inflammatory drugs (NSAIDs) and for the COX-2-selective inhibitors, celecoxib and rofecoxib. NSAIDs exhibit varying selectivity for COX-2 and COX-1 but, in general, none of them displays high selectivity for COX-2. NSAIDs and COX-2-selective inhibitors possess cancer chemopreventive activity, retard the growth of human tumor xenografts in nude mice, and induce polyp regression in individuals with familial polyposis. These activities have been attributed to their ability to inhibit COX-2. The elevated expression of COX-2 in benign and malignant tumors and the apparent functional role that the enzyme plays in tumor growth suggests that COX-2 is an attractive target for the development of tumor-selective imaging agents. Our laboratory has developed a novel approach that allows the facile conversion of non-selective NSAIDs into highly selective COX-2 inhibitors. This is accomplished by conversion of the carboxylic acid functional group, common to most NSAIDs, to an amide or ester. Extensive structure-activity studies indicate that a diverse range of functional groups can be tethered to an NSAID through a stable amide linkage with retention of potency and selectivity for COX-2 inhibition. Indeed, it is extremely rare that the specific binding of an enzyme inhibitor allows such a wide range of structural flexibility. Jashim is interested in developing fluorescent or radiolabeled COX-2-targeted agents that selectively label COX-2 expressing tumor cells in vitro and in vivo. COX-2-selective imaging agents can be developed specifically for use with the optical modalities, near infrared (NIR) fluoresecence and two-photon microscopy, and the radiologic modalities, SPECT and PET, and that these agents can be used to monitor COX-2 expression during tumor initiation and progression. These imaging approaches lead to determine the predictive value of COX-2 expression on the response to therapy, the effects of therapy on COX-2 expression, and the usefulness of imaging to design therapy based on COX-2 inhibition. The results of these experiments will form the framework for the rapid development of COX-2-targeted imaging agents for the clinical cancer detection in the early stage.
Research Keywords
Fluorescent and radiolabeled cyclooxygense-2 inhibitors; in vivo imaging; structural basis, pharmacokinetics and metabolism.
Publications
Bedse G, Hartley ND, Neale E, Gaulden AD, Patrick TA, Kingsley PJ, Uddin MJ, Plath N, Marnett LJ, Patel S. Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety. Biol. Psychiatry [print-electronic]. 2017 Oct 10/1/2017; 82(7): 488-99. PMID: 28438413, PMCID: PMC5585044, PII: S0006-3223(17)31357-4, DOI: 10.1016/j.biopsych.2017.03.002, ISSN: 1873-2402.

Bluett RJ, Báldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S. Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun. 2017 Mar 3/28/2017; 8: 14782. PMID: 28348378, PMCID: PMC5379055, PII: ncomms14782, DOI: 10.1038/ncomms14782, ISSN: 2041-1723.

Foster DJ, Wilson JM, Remke DH, Mahmood MS, Uddin MJ, Wess J, Patel S, Marnett LJ, Niswender CM, Jones CK, Xiang Z, Lindsley CW, Rook JM, Conn PJ. Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release. Neuron [print-electronic]. 2016 Sep 9/21/2016; 91(6): 1244-52. PMID: 27618677, PII: S0896-6273(16)30509-8, DOI: 10.1016/j.neuron.2016.08.017, ISSN: 1097-4199.

Uddin MJ, Crews BC, Xu S, Ghebreselasie K, Daniel CK, Kingsley PJ, Banerjee S, Marnett LJ. Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors. ACS Chem. Biol [print-electronic]. 2016 Sep 9/19/2016; PMID: 27588346, DOI: 10.1021/acschembio.6b00560, ISSN: 1554-8937.

Uddin MJ, Moore CE, Crews BC, Daniel CK, Ghebreselasie K, McIntyre JO, Marnett LJ, Jayagopal A. Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization. J Biomed Opt. 2016 Sep 9/1/2016; 21(9): 90503. PMID: 27626899, PII: 2553360, DOI: 10.1117/1.JBO.21.9.090503, ISSN: 1560-2281.

Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM. Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. J. Med. Chem [print-electronic]. 2016 Aug 8/25/2016; 59(16): 7431-44. PMID: 27486833, DOI: 10.1021/acs.jmedchem.6b00160, ISSN: 1520-4804.

Uddin MJ, Werfel TA, Crews BC, Gupta MK, Kavanaugh TE, Kingsley PJ, Boyd K, Marnett LJ, Duvall CL. Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer. Biomaterials [print-electronic]. 2016 Jun; 92: 71-80. PMID: 27043768, PMCID: PMC4833621, PII: S0142-9612(16)30049-7, DOI: 10.1016/j.biomaterials.2016.03.028, ISSN: 1878-5905.

Uddin MI, Evans SM, Craft JR, Capozzi ME, McCollum GW, Yang R, Marnett LJ, Uddin MJ, Jayagopal A, Penn JS. In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy. Sci Rep. 2016; 6: 31011. PMID: 27491345, PMCID: PMC4974503, PII: srep31011, DOI: 10.1038/srep31011, ISSN: 2045-2322.

Wilson AJ, Fadare O, Beeghly-Fadiel A, Son DS, Liu Q, Zhao S, Saskowski J, Uddin MJ, Daniel C, Crews B, Lehmann BD, Pietenpol JA, Crispens MA, Marnett LJ, Khabele D. Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer. Oncotarget. 2015 Aug 8/28/2015; 6(25): 21353-68. PMID: 25972361, PMCID: PMC4673270, PII: 3860, DOI: 10.18632/oncotarget.3860, ISSN: 1949-2553.

Uddin MI, Evans SM, Craft JR, Marnett LJ, Uddin MJ, Jayagopal A. Applications of azo-based probes for imaging retinal hypoxia. ACS Med Chem Lett. 2015 Apr 4/9/2015; 6(4): 445-9. PMID: 25893047, PMCID: PMC4394343, DOI: 10.1021/ml5005206, ISSN: 1948-5875.

Ra H, González-González E, Uddin MJ, King BL, Lee A, Ali-Khan I, Marnett LJ, Tang JY, Contag CH. Detection of non-melanoma skin cancer by in vivo fluorescence imaging with fluorocoxib A. Neoplasia. 2015 Feb; 17(2): 201-7. PMID: 25748239, PMCID: PMC4351298, PII: S1476-5586(14)00199-7, DOI: 10.1016/j.neo.2014.12.009, ISSN: 1476-5586.

Uddin MJ, Elleman AV, Ghebreselasie K, Daniel CK, Crews BC, Nance KD, Huda T, Marnett LJ. Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors. ACS Med Chem Lett. 2014 Nov 11/13/2014; 5(11): 1254-8. PMID: 25408841, PMCID: PMC4233350, DOI: 10.1021/ml500344j, ISSN: 1948-5875.

Perrone MG, Malerba P, Uddin MJ, Vitale P, Panella A, Crews BC, Daniel CK, Ghebreselasie K, Nickels M, Tantawy MN, Manning HC, Marnett LJ, Scilimati A. PET radiotracer [¹8F]-P6 selectively targeting COX-1 as a novel biomarker in ovarian cancer: preliminary investigation. Eur J Med Chem [print-electronic]. 2014 Jun 6/10/2014; 80: 562-8. PMID: 24832612, PMCID: PMC4401082, PII: S0223-5234(14)00403-6, DOI: 10.1016/j.ejmech.2014.04.074, ISSN: 1768-3254.

Uddin MJ, Crews BC, Huda I, Ghebreselasie K, Daniel CK, Marnett LJ. Trifluoromethyl fluorocoxib a detects cyclooxygenase-2 expression in inflammatory tissues and human tumor xenografts. ACS Med Chem Lett. 2014 Apr 4/10/2014; 5(4): 446-50. PMID: 24900856, PMCID: PMC4027729, DOI: 10.1021/ml400485g, ISSN: 1948-5875.

Blobaum AL, Uddin MJ, Felts AS, Crews BC, Rouzer CA, Marnett LJ. The 2'-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor. ACS Med Chem Lett [print-electronic]. 2013 May 5/9/2013; 4(5): 486-90. PMID: 23687559, PMCID: PMC3654564, DOI: 10.1021/ml400066a, ISSN: 1948-5875.

Uddin MJ, Crews BC, Ghebreselasie K, Marnett LJ. Design, synthesis, and structure-activity relationship studies of fluorescent inhibitors of cycloxygenase-2 as targeted optical imaging agents. Bioconjug. Chem [print-electronic]. 2013 Apr 4/17/2013; 24(4): 712-23. PMID: 23488616, PMCID: PMC3630741, DOI: 10.1021/bc300693w, ISSN: 1520-4812.

Uddin MJ, Crews BC, Ghebreselasie K, Huda I, Kingsley PJ, Ansari MS, Tantawy MN, Reese J, Marnett LJ. Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer. Cancer Prev Res (Phila) [print-electronic]. 2011 Oct; 4(10): 1536-45. PMID: 21900596, PMCID: PMC3214660, PII: 1940-6207.CAPR-11-0120, DOI: 10.1158/1940-6207.CAPR-11-0120, ISSN: 1940-6215.

Uddin MJ, Schulte MI, Maddukuri L, Harp J, Marnett LJ. Semisynthesis of 6-chloropurine-2'-deoxyriboside 5'-dimethoxytrityl 3'-(2-cyanoethyl-N,N-diisopropylamino)phosphoramidite and its use in the synthesis of fluorescently labeled oligonucleotides. Nucleosides Nucleotides Nucleic Acids. 2010 Nov; 29(11): 831-40. PMID: 21128170, PMCID: PMC3019237, PII: 930388354, DOI: 10.1080/15257770.2010.530332, ISSN: 1532-2335.

Uddin MJ, Crews BC, Blobaum AL, Kingsley PJ, Gorden DL, McIntyre JO, Matrisian LM, Subbaramaiah K, Dannenberg AJ, Piston DW, Marnett LJ. Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents. Cancer Res. 2010 May 5/1/2010; 70(9): 3618-27. PMID: 20430759, PMCID: PMC2864539, PII: 70/9/3618, DOI: 10.1158/0008-5472.CAN-09-2664, ISSN: 1538-7445.

Uddin MJ, Smithson DC, Brown KM, Crews BC, Connelly M, Zhu F, Marnett LJ, Guy RK. Podophyllotoxin analogues active versus Trypanosoma brucei. Bioorg. Med. Chem. Lett [print-electronic]. 2010 Mar 3/1/2010; 20(5): 1787-91. PMID: 20129783, PMCID: PMC2826502, PII: S0960-894X(10)00011-9, DOI: 10.1016/j.bmcl.2010.01.009, ISSN: 1464-3405.

Konkle ME, Hargrove TY, Kleshchenko YY, von Kries JP, Ridenour W, Uddin MJ, Caprioli RM, Marnett LJ, Nes WD, Villalta F, Waterman MR, Lepesheva GI. Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase. J. Med. Chem. 2009 May 5/14/2009; 52(9): 2846-53. PMID: 19354253, PMCID: PMC2744100, DOI: 10.1021/jm801643b, ISSN: 1520-4804.

Uddin, M. J., Crews, B. C., Blobaum, A. L., Kingslay, P. J., Ghebraselase, K., Saleh, S. S., Clanton, J. A., Baldwin, R. M. and Marnett, L. J.. Synthesis and evaluation of [123I]-indomethacin derivatives as COX-2 targeted imaging agents. Journal of Labelled Compounds and Radiopharmaceuticals. 2009; 52: 387-93.

Uddin MJ, Marnett LJ. Synthesis of 5- and 6-carboxy-X-rhodamines. Org. Lett [print-electronic]. 2008 Nov 11/6/2008; 10(21): 4799-801. PMID: 18837556, PMCID: PMC2646678, DOI: 10.1021/ol801904k, ISSN: 1523-7052.

Anning, P. B.; Coles, B; Morton, J.; Wang, H.; Uddin, M. J.; Morrow, J. D.; Dey, S. K.; Marnett, L. J.; Odonnell, V. B.. Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors. Blood. 2006; 13: 4059.

Uddin MJ, Rao PN, McDonald R, Knaus EE. Design and synthesis of (E)-1,1,2-triarylethenes: novel inhibitors of the cyclooxygenase-2 (COX-2) isozyme. Bioorg. Med. Chem. Lett. 2005 Jan 1/17/2005; 15(2): 439-42. PMID: 15603969, PII: S0960-894X(04)01291-0, DOI: 10.1016/j.bmcl.2004.10.050, ISSN: 0960-894X.

Uddin MJ, Praveen Rao PN, Knaus EE. Design and synthesis of (Z)-1,2-diphenyl-1-(4-methanesulfonamidophenyl)alk-1-enes and (Z)-1-(4-azidophenyl)-1,2-diphenylalk-1-enes: novel inhibitors of cyclooxygenase-2 (COX-2) with anti-inflammatory and analgesic activity. Bioorg. Med. Chem. 2005 Jan 1/17/2005; 13(2): 417-24. PMID: 15598562, PII: S0968-0896(04)00791-6, DOI: 10.1016/j.bmc.2004.10.017, ISSN: 0968-0896.

Uddin MJ, Praveen Rao PN, McDonald R, Knaus EE. A new class of acyclic 2-alkyl-1,1,2-triaryl (Z)-olefins as selective cyclooxygenase-2 inhibitors. J. Med. Chem. 2004 Nov 11/18/2004; 47(24): 6108-11. PMID: 15537365, DOI: 10.1021/jm049523y, ISSN: 0022-2623.

Uddin MJ, Rao PN, Knaus EE. Design and synthesis of acyclic triaryl (Z)-olefins: a novel class of cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. 2004 Nov 11/15/2004; 12(22): 5929-40. PMID: 15498669, PII: S0968-0896(04)00624-8, DOI: 10.1016/j.bmc.2004.08.021, ISSN: 0968-0896.

Uddin MJ, Rao PN, Rahim MA, McDonald R, Knaus EE. A new class of acyclic 2-alkyl-1,2-diaryl (E)-olefins as selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. Lett. 2004 Oct 10/4/2004; 14(19): 4911-4. PMID: 15341950, PII: S0960-894X(04)00919-9, DOI: 10.1016/j.bmcl.2004.07.027, ISSN: 0960-894X.

Rao PN, Uddin MJ, Knaus EE. Design, synthesis, and structure-activity relationship studies of 3,4,6-triphenylpyran-2-ones as selective cyclooxygenase-2 inhibitors. J. Med. Chem. 2004 Jul 7/29/2004; 47(16): 3972-90. PMID: 15267236, DOI: 10.1021/jm049939b, ISSN: 0022-2623.

Uddin MJ, Rao PN, Knaus EE. Design of acyclic triaryl olefins: a new class of potent and selective cyclooxygenase-2 (COX-2) inhibitors. Bioorg. Med. Chem. Lett. 2004 Apr 4/19/2004; 14(8): 1953-6. PMID: 15050635, PII: S0960894X04001556, DOI: 10.1016/j.bmcl.2004.01.075, ISSN: 0960-894X.

Uddin, M. J.; Rao, P. N. P.; Knaus, E. E.. Methylsulfonyl and Hydroxyl Substituents Induce (Z)-Stereocontrol in the McMurry Olefination Reaction. Synlett. 2004; 1513.

Uddin MJ, Rao PN, Knaus EE. Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere. Bioorg. Med. Chem. 2003 Nov 11/17/2003; 11(23): 5273-80. PMID: 14604691, PII: S0968089603005583, ISSN: 0968-0896.

Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Design, Synthesis and Biological Evaluation of Novel Rofecoxib Analogs as Potential Cyclooxygenase-2 (COX-2) Inhibitors: Replacement of Methylsulfonyl Pharmacophore by a Sulfonylazide Bioisostre. Journal of Heterocyclic Chemistry. 2003; 40: 861.

Uddin, M. J.; Kikuchi, M.; Takedatsu, K.; Arai, K.-I.; Fujimoto, T.; Motoyoshiya, J.; Kakehi, A.; Iriue, R.; Shirai, H.; Yamamoto, I.. Synthesis and Structure of Condensed Heterocycles Derived from Intramolecular 1,3-Dipolar Cycloaddition of Transient and Enantiomerically Pure ?-Allylamino Nitrones and Nitrile Oxides in a High Level of Diastereoselectivity. Synthesis. 2000; 365.

Uddin, M. J.; Fujimoto, T.; Kakehi, A.; Shirai, H.; Yamamoto, I.. Diastereoselective Synthesis of Bridgehead Heterocyclic Spiro Compounds Derived from Tandem Michael Intramolecular 1,3-Dipolar Cycloaddition of Nitrones. Heterocyclic Communications. 2000; 6: 113.

Uddin, M. J.; Shinooka, A.; Fujimoto, T.; Shirai, H.; Yamamoto, I.. Isoxazolidine Based New Chral Auxiliary for Asymmetric Synthesis. Heterocyclic Communications. 2000; 6: 505.