Mahesh Pattabiraman

Speciation, formation, stability and analytical challenges of human arsenic metabolites

Human arsenic metabolism produces a number of species with varying toxicities; the presence of some has been identified while the existence of others has been postulated through indirect evidence. Speciation methods for the analysis of arsenite (AsIII), monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII), arsenate (AsV), monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), arsino-glutathione (As(GS)3), monomethylarsino-glutathione (MMA(GS)2) and dimethylarsino-glutathione (DMA(GS)) were developed in this study through the use of cation exchange and reverse phase chromatography in a complementary manner. Electrospray ionization mass spectrometry (ESI-MS) was used for molecular identification of the arsenicals while inductively coupled plasma mass spectrometry (ICP-MS) was employed for quantitation purposes. Validation of the developed methods against each other for the quantitation of trivalent and pentavalent arsenicals was performed. The effect of reduced glutathione (GSH) concentration on the formation of arsenic-glutathione (As-GSH) complexes was studied. In the presence of glutathione, the occurrence of chromatographic artifacts on the cation exchange column was observed. The stability of trivalent arsenicals and As-GSH complexes was studied at various pH conditions. The results shed light on the importance of sample preparation, storage and proper choice of analytical column for the accurate identification of the As species. Reinvestigation of some of the previously reported As speciation studies of glutathione-rich biological samples needs to be performed for the verification of occurrence of As-GSH complexes and DMAIII.

Regioselective photodimerization of pyridyl-butadienes within cucurbit[8]uril cavities

The cucurbit[8]uril (CB8) templation strategy that is known to yield stereoselective photodimers of organic olefins has been extended to substituted butadienes. By virtue of its strong binding interactions with guests the rigid cavity of CB8 is capable of preorienting the diene guests to result in greater yields of stereoselective photodimers upon irradiation. The symmetry of the butadiene monomers influences the relative arrangement of the monomers in complexes leading to the observed product selectivity.

Using non-covalent interactions to direct regioselective 2+2 photocycloaddition within a macrocyclic cavitand

The relative orientation of guests within ternary inclusion complexes is governed by the host–guest and guest–guest supramolecular interactions. Selectivity in 2+2 photocycloaddition between two alkenes included within a macrocyclic cavitand (γ-cyclodextrin) can be controlled using non-covalent interactions. In this manuscript, we report cavitand-mediated control of regioselectivity between alkyl cinnamates using non-covalent interactions. Using this method, we have shown that regioselectivity can be switched completely from a head-to-head dimer to a head-to-tail dimer. The reactions were also stereoselective in most cases. Stoichiometry experiments were performed to explore relative stabilities of the complexes, which indicate that the ternary complex is more stable than others. Selectivity in the photocycloaddition reaction was also applied retrospectively to deduce intermolecular orientations. Time-dependent conversion study we performed indicates that the observed reactivity of alkenes is representative of the intermolecular orientations in the bulk of the complex medium. Experimental observations and computational studies were used to qualitatively understand the complex structures, and relative magnitudes of the weak interactions. The reactions of complexes were studied in slurry form, and the extent of reaction control suggests a solid-state-like behavior.

Ferulic acid dimer as a non-opioid therapeutic for acute pain

Purpose Search for alternate pain medications has gained more importance in the past few years due to adverse effects associated with currently prescribed drugs including nervous system dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has been explored for the treatment of pain, as these have been used for generations in regional communities and tend to lack major side effects in general. One such phytomedicine, incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis has its primary antinociceptive action through the adenosine receptor, a novel pain target. We hypothesized that derivatives of cinnamic acid dimers, which are structurally similar to INCA, would show potent antinociceptive action and that their effect would be mediated through adenosine receptor action. Materials and methods Dimers of cinnamic acid (INCA analogs) were synthesized using cavitand-mediated photodimerization (CMP) method, which utilizes a macromolecule (γ-cyclodextrin) to control excited state reactivity of photoactive compounds. Acute pain response was assessed by using formalin-induced licking behavior in hind paw of mice, and neurologic function was monitored through locomotor activity, mechanical hyperalgesia, and thermal sensitivity upon administration of test compound. For mechanistic studies, binding to adenosine receptor was determined by using computer modeling. Results Ferulic acid dimer (FAD), which has the same chemical functionalities on the aromatic ring as INCA, showed significant suppression of formalin-induced acute pain. Antinociceptive effect was observed primarily in the inflammatory phase, and no apparent behavioral changes related to the nervous system were noticeable. Inhibition of opioid receptor did not reverse antinociceptive response, and modeling data suggest adenosine 3 receptor binding. Conclusion FAD (INCA analog) shows potent nonopioid antinociceptive action mediated predominantly through A3AR – adenosine 3 receptor action. Further characterization and selection of such INCA analogs will help us generate a new class of antinociceptives with precise chemical modifications by using CMP methodology.

Antineoplastic Actions of Cinnamic Acids and Their Dimers in Breast Cancer Cells: A Comparative Study

Background/Aim: Breast cancer is the second leading cause of cancer-related deaths in US, which necessitates constant research for medications with minimal adverse effects. The aim of the study was to determine if certain cinnamic acid dimers (CADs) exhibit higher cytotoxicity in breast cancer cells than against non-tumorigenic cells. Materials and Methods: These dimers have not been explored, so far, due to their complex stereochemistry; cavitand-mediated photodimerization (CMP) method was used to produce several CADs, which were tested for cytotoxicity, apoptosis and cell cycle inhibition. Results: CADs such as ferulic acid dimer, 3-fluoro CAD, and 3, 4-difluoro CAD, were found to be more cytotoxic than their parent monomers. The most potent compound, 3-fluoro CAD caused apoptosis and ‘S’ phase cell cycle arrest in cancer cells. Conclusion: This study indicates an avenue for research for developing a novel class of antineoplastic compounds that can be synthesized using an easy, economical method.