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Dive into the research topics where Mathangi Krishnamurthy is active.

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Featured researches published by Mathangi Krishnamurthy.


Nature | 2008

Template-directed Synthesis of a Genetic Polymer in a Model Protocell

Sheref S. Mansy; Jason P. Schrum; Mathangi Krishnamurthy; Sylvia Tobe; Douglas A. Treco; Jack W. Szostak

Contemporary phospholipid-based cell membranes are formidable barriers to the uptake of polar and charged molecules ranging from metal ions to complex nutrients. Modern cells therefore require sophisticated protein channels and pumps to mediate the exchange of molecules with their environment. The strong barrier function of membranes has made it difficult to understand the origin of cellular life and has been thought to preclude a heterotrophic lifestyle for primitive cells. Although nucleotides can cross dimyristoyl phosphatidylcholine membranes through defects formed at the gel-to-liquid transition temperature, phospholipid membranes lack the dynamic properties required for membrane growth. Fatty acids and their corresponding alcohols and glycerol monoesters are attractive candidates for the components of protocell membranes because they are simple amphiphiles that form bilayer membrane vesicles that retain encapsulated oligonucleotides and are capable of growth and division. Here we show that such membranes allow the passage of charged molecules such as nucleotides, so that activated nucleotides added to the outside of a model protocell spontaneously cross the membrane and take part in efficient template copying in the protocell interior. The permeability properties of prebiotically plausible membranes suggest that primitive protocells could have acquired complex nutrients from their environment in the absence of any macromolecular transport machinery; that is, they could have been obligate heterotrophs.


Journal of the American Chemical Society | 2009

Efficient and Rapid Template-Directed Nucleic Acid Copying Using 2′-Amino-2′,3′-dideoxyribonucleoside−5′-Phosphorimidazolide Monomers

Jason P. Schrum; Alonso Ricardo; Mathangi Krishnamurthy; J. Craig Blain; Jack W. Szostak

The development of a sequence-general nucleic acid copying system is an essential step in the assembly of a synthetic protocell, an autonomously replicating spatially localized chemical system capable of spontaneous Darwinian evolution. Previously described nonenzymatic template-copying experiments have validated the concept of nonenzymatic replication, but have not yet achieved robust, sequence-general polynucleotide replication. The 5′-phosphorimidazolides of the 2′-amino-2′,3′-dideoxyribonucleotides are attractive as potential monomers for such a system because they polymerize by forming 2′→5′ linkages, which are favored in nonenzymatic polymerization reactions using similarly activated ribonucleotides on RNA templates. Furthermore, the 5′-activated 2′-amino nucleotides do not cyclize. We recently described the rapid and efficient nonenzymatic copying of a DNA homopolymer template (dC15) encapsulated within fatty acid vesicles using 2′-amino-2′,3′-dideoxyguanosine−5′-phosphorimidazolide as the activated monomer. However, to realize a true Darwinian system, the template-copying chemistry must be able to copy most sequences and their complements to allow for the transmission of information from generation to generation. Here, we describe the copying of a series of nucleic acid templates using 2′-amino-2′,3′-dideoxynucleotide−5′-phosphorimidazolides. Polymerization reactions proceed rapidly to completion on short homopolymer RNA and LNA templates, which favor an A-type duplex geometry. We show that more efficiently copied sequences are generated by replacing the adenine nucleobase with diaminopurine, and uracil with C5-(1-propynyl)uracil. Finally, we explore the copying of longer, mixed-sequence RNA templates to assess the sequence-general copying ability of 2′-amino-2′,3′-dideoxynucleoside−5′-phosphorimidazolides. Our results are a significant step forward in the realization of a self-replicating genetic polymer compatible with protocell template copying and suggest that N2′→P5′-phosphoramidate DNA may have the potential to function as a self-replicating system.


Bioorganic & Medicinal Chemistry Letters | 2003

Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids

Mathangi Krishnamurthy; Antonio M. Ferreira; Bob M. Moore

A series of novel phenyl substituted side-chain analogues of classical cannabinoids were synthesized and their CB1 and CB2 binding affinities were evaluated relative to Delta(8)-THC and compound 2. CB1 and CB2 binding assays indicate that the dimethyl and ketone analogues (3) and (6) display selectivity for the CB2 receptor in comparison to delta(8)-THC and compound 2. This study provides newer insights into the geometrical and functional group requirements of the ligand binding pockets of the CB1 and the CB2 receptors.


Journal of Neuro-oncology | 2006

Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma

Christopher Duntsch; Murali Krishna Divi; Terreia S. Jones; Qihong Zhou; Mathangi Krishnamurthy; Peter Boehm; George C. Wood; Allen K. Sills; Bob M. Moore

SummaryObjectiveTo test in vitro and in vivo the safety and efficacy of a novel chemotherapeutic agent, KM-233, for the treatment of glioma.MethodsIn vitro cell cytotoxicity assays were used to measure and compare the cytotoxic effects of KM-233, Δ8-tetrahydrocannabinol (THC), and bis-chloroethyl-nitrosurea (BCNU) against human U87 glioma cells. An organotypic brain slice culture model was used for safety and toxicity studies. A human glioma-SCID mouse side-pocket tumor model was used to test in vivo the safety and efficacy of KM-233 with intratumoral and intra-peritoneal administration.ResultsKM-233 is a classical cannabinoid with good blood brain barrier penetration that possesses a selective affinity for the CB2 receptors relative to THC. KM-233 was as efficacious in its cytotoxicity against human U87 glioma as Δ8-tetrahydrocannabinol, and superior to the commonly used anti-glioma chemotherapeutic agent, BCNU. The cytotoxic effects of KM-233 against human glioma cells in vitro occur as early as two hours after administration, and dosing of KM-233 can be cycled without compromising cytotoxic efficacy and while improving safety. Cyclical dosing of KM-233 to treat U87 glioma in a SCID mouse xenograft side pocket model was effective at reducing the tumor burden with both systemic and intratumoral administration.ConclusionThese studies provide both in vitro and in vivo evidence that KM-233 shows promising efficacy against human glioma cell lines in both in vitro and in vivo studies, minimal toxicity to healthy cultured brain tissue, and should be considered for definitive preclinical development in animal models of glioma.


Bioorganic & Medicinal Chemistry | 2003

Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors.

Asha Nadipuram; Mathangi Krishnamurthy; Antonio M. Ferreira; Wei Li; Bob M. Moore

A series of C3 cyclic side-chain analogues of classical cannabinoids were synthesized to probe the ligand binding pocket of the CB1 and CB2 receptors. The analogues were evaluated for CB1 and CB2 receptor binding affinities relative to delta(8)-THC. The C3 side-chain geometries of the analogues were studied using high field NMR spectroscopy and quantum mechanical calculations. The results of these studies provide insights into the geometry of the ligand binding pocket of the CB1 and CB2 receptors.


Bioorganic & Medicinal Chemistry | 2009

Quantitative structure-activity relationship (QSAR) for a series of novel cannabinoid derivatives using descriptors derived from semi-empirical quantum-chemical calculations

Antonio M. Ferreira; Mathangi Krishnamurthy; Bob M. Moore; David Finkelstein; Donald Bashford

Recent work implicating the cannabinoid receptors in a wide range of human pathologies has intensified the need for reliable QSAR models for drug discovery and lead optimization. Predicting the ligand selectivity of the cannabinoid CB(1) and CB(2) receptors in the absence of generally accepted models for their structures requires a ligand-based approach, which makes such studies ideally suited for quantum-chemical treatments. We present a QSAR model for ligand-receptor interactions based on quantum-chemical descriptors (an eQSAR) obtained from PM3 semi-empirical calculations for a series of phenyl-substituted cannabinoids based on a ligand with known in vivo activity against glioma [Duntsch, C.; Divi, M. K.; Jones, T.; Zhou, Q.; Krishnamurthy, M.; Boehm, P.; Wood, G.; Sills, A.; Moore. B. M., II. J. Neuro-Oncol., 2006, 77, 143] and a set of structurally similar adamantyl-substituted cannabinoids. A good model for CB(2) inhibition (R(2)=0.78) has been developed requiring only four explanatory variables derived from semi-empirical results. The role of the ligand dipole moment is discussed and we propose that the CB(2) binding pocket likely possesses a significant electric field. Describing the affinities with respect to the CB(1) receptor was not possible with the current set of ligands and descriptors, although the attempt highlighted some important points regarding the development of QSAR models.


Bioorganic & Medicinal Chemistry | 2004

Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands.

Mathangi Krishnamurthy; Wei Li; Bob M. Moore


Archive | 2004

Cannabinoid derivatives, methods of making, and use thereof

Bob M. Moore; Antonio M. Ferreira; Mathangi Krishnamurthy


Bioorganic & Medicinal Chemistry | 2008

Exploring the substituent effects on a novel series of C1′-dimethyl-aryl Δ8-tetrahydrocannabinol analogs

Mathangi Krishnamurthy; Steven Gurley; Bob M. Moore


Journal of Molecular Structure-theochem | 2004

Theoretical analysis of the NMR and electronic structure of novel Δ8-THC derivatives

Antonio M. Ferreira; Bob M. Moore; Mathangi Krishnamurthy

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Bob M. Moore

University of Tennessee Health Science Center

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Antonio M. Ferreira

St. Jude Children's Research Hospital

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Jason P. Schrum

Howard Hughes Medical Institute

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Wei Li

University of Tennessee Health Science Center

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Alonso Ricardo

Howard Hughes Medical Institute

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Asha Nadipuram

University of Tennessee Health Science Center

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Christopher Duntsch

University of Tennessee Health Science Center

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David Finkelstein

St. Jude Children's Research Hospital

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