Assistant Professor, Department of Pharmacy, Tripura University (A Central University), Surymaninagar, India
Anticancer drug discovery
LIPIDS: A CULPRIT OR SAVIOR?
Why lipids are culprit?
We often fear when we hear the word “lipid” in relation to our health. This fear is quite normal because of the terrifying risks associated with the elevated levels of lipids in blood circulation. If we simply Google the key words “Lipids + Disease”, then almost all cardiovascular, renal, cerebral and hormonal diseases are going to pop-up on your computer screen. So, it is obvious that we must avoid lipids in our diets for a good health. But, then the question is why lipid even exists in our body when it is bad for health? The pursuit for the answer of this question gave new insights for my research area. If excessive lipid can create disease in human body, then it can also alter diseases if handled rightfully.
How lipids can be savior?
Our body cells are made up of a specialized lipids or a derived lipid known as phospholipids. The medicines that we take in disease conditions need to penetrate these lipid membranes in order to modify the diseases. There are several research which emphasize that individual cells within the body produces bioactive lipid signaling that allows the cells to 'see' the surrounding environment and to respond in ways that will benefit the whole body. Therefore, drugs that can reach these bioactive lipid targets will also produce successful drug candidates.
What we do to defend lipids?
My current drug discovery research work is focused on development of new drug candidates for the treatment of inoperable cancers like leukemia, colon and lung cancer. To achieve this objective, we have synthesized several lipidised bioactive molecules and tested them against several human cancer cell lines. One such example is the lipidisation of antioxidant molecules with other derived lipids like steroid hormones and fatty acids. These molecules have exhibited strong antineoplastic properties. We have also successfully synthesized several 16-arylidene steroid derivatives as highly selective antileukemic agents [Steroids 2012, 77, 552-557; Arch. Pharm. Chem. Life Sci. 2014, 347, 193-199]. Few bioconjugates of steroids and alkylating agents has also been developed as potent antineoplastic agents using similar approach and found to have tremendous biological activity with no or lesser toxicity.
Abstract: Embodiments provided herewith relate to methods and compositions for treating or preventing cancer. More particularly, several embodiments are drawn to treating or preventing malignant mesothelioma with antagonists of high-mobility group box 1 (HMGB1).
Pub.: 07 Feb '17, Pinned: 17 Aug '17
Abstract: Lipid metabolism has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS). With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research. We used unsupervised machine-learning to analyze lipid marker serum concentrations, pursuing the hypothesis that for the most relevant markers the emerging data structures will coincide with the diagnosis of MS. Machine learning was implemented as emergent self-organizing feature maps (ESOM) combined with the U*-matrix visualization technique. The data space consisted of serum concentrations of three main classes of lipid markers comprising eicosanoids (d = 11 markers), ceramides (d = 10), and lyosophosphatidic acids (d = 6). They were analyzed in cohorts of MS patients (n = 102) and healthy subjects (n = 301). Clear data structures in the high-dimensional data space were observed in eicosanoid and ceramides serum concentrations whereas no clear structure could be found in lysophosphatidic acid concentrations. With ceramide concentrations, the structures that had emerged from unsupervised machine-learning almost completely overlapped with the known grouping of MS patients versus healthy subjects. This was only partly provided by eicosanoid serum concentrations. Thus, unsupervised machine-learning identified distinct data structures of bioactive lipid serum concentrations. These structures could be superimposed with the known grouping of MS patients versus healthy subjects, which was almost completely possible with ceramides. Therefore, based on the present analysis, ceramides are first-line candidates for further exploration as drug-gable targets or biomarkers in MS.
Pub.: 08 Jun '17, Pinned: 17 Aug '17
Abstract: Sphingolipids belong to a complex class of lipid molecules that are crucially involved in the regulation of important biological processes including proliferation, migration and apoptosis. Given the significant progress made in understanding the sphingolipid pathobiology of several diseases, sphingolipid-related checkpoints emerge as attractive targets. Recent data indicate the multifaceted contribution of the sphingolipid machinery to osteoclast - osteoblast crosstalk, representing one of the pivotal interactions underlying bone homeostasis. Imbalances in the interplay of osteoblasts and osteoclasts might lead to bone-related diseases such as osteoporosis, rheumatoid arthritis and bone metastases. Areas covered: We summarize and analyze the progress made in bone research in the context of the current knowledge of sphingolipid-related mechanisms regulating bone remodeling. Particular emphasis was given to bioactive sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs). Moreover, the mechanisms of how dysregulations of this machinery cause bone diseases, are covered. Expert opinion: In the context of bone diseases, pharmacological interference with sphingolipid machinery may lead to novel directions in therapeutic strategies. Implementation of knowledge derived from in vivo animal models and in vitro studies using pharmacological agents to manipulate the S1P/S1PRs axes suggests S1PR2 and S1PR3 as potential drug targets, particularly in conjunction with technology for local drug delivery.
Pub.: 20 May '17, Pinned: 17 Aug '17
Abstract: Neuroinflammatory mechanisms mediated by activated glial and cytokines (TNF-α, IL-1β) might contribute neuronal degeneration leading to Alzheimer's (AD) and Parkinson's disease (PD). Lipopolysaccharide (LPS) is an inflammogen derived from the cell wall of Gram-negative bacteria, which promotes neuroinflammation and subsequent neurodegeneration. Dehydroepiandrosterone (DHEA) and testosterone have been reported as neuroprotective steroids useful for the treatment of various neurodegenerative disorders. In the present study, several 16-arylidene steroidal derivatives have been evaluated as neuroprotective agents in LPS-treated animal models. It was observed that 16-arylidene steroidal derivatives 1a-d and 6a-h considerably improve LPS-induced learning, memory and movement deficits in animal models. Biochemical estimations of brain serum of treated animals revealed suppression of oxidative and nitrosative stress, acetylcholinesterase activity and reduction in TNF-α levels, which were induced through LPS mediated neuroinflammatory mechanism leading to neurodegeneration of brain. Of all the steroidal derivatives, 16-(4-pyridylidene) steroid 1c and its 4-aza analogue 6c were found to be the most active neuroprotective agents and produced effects comparable to standard drug celecoxib at a much lower dose and better than dexamethasone at the same dose in terms of behavioural, biochemical and molecular aspects. Key words: Parkinson's disease, Alzheimer's disease, neuroinflammation, 16-arylidene steroids.
Pub.: 25 Oct '16, Pinned: 09 Aug '17
Abstract: In the present study, synthesis and antineoplastic activity of phenylacetic acid and benzoic acid nitrogen mustard conjugates of various steroidal oximes are reported for the first time. The conjugation was achieved through a more stable oxime-ester linkage and the resulting newly synthesized conjugates were evaluated in vitro on various human cancer cell lines for cytotoxicity. The extent of their alkylating activity was investigated by the in vitro colorimetric 4-(p-nitrobenzyl)pyridine (NBP) assay. The 17E-steroidal oxime-benzoic acid mustard ester 3β-acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino)]benzoyloxyimino-androst-5-ene (8) emerged as the most potent conjugate having significant cytotoxicity on most of the NCI 60-cell lines. Outstanding growth inhibition was observed on the IGROV1 ovarian cancer cell line with GI50 = 0.937 µM. In general, the D-ring derived androstene oxime-nitrogen mustard conjugates were found to possess better antineoplastic activity over a variety of cancer cells in comparison to those derived from other rings of the steroid skeleton.
Pub.: 25 Apr '17, Pinned: 03 Jul '17
Abstract: In order to study the structure-activity relationship with respect to the cytotoxicity of steroidal oximes, several 6E-hydroximino-4-ene steroids and their O-alkylated derivatives were synthesized. The oxime ethers were solidified and purified by preparing their corresponding oxalate salts. The new derivatives as well as some previously synthesized ones were evaluated for in vitro antineoplastic activity against a panel of 60 cancer cell lines at 10 µM. The oximes and oxime ethers were found to have moderate to good antiproliferative activity against various leukemia, colon, melanoma, and renal cancer cell lines.
Pub.: 18 Dec '13, Pinned: 09 Aug '17
Abstract: The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.
Pub.: 15 Apr '16, Pinned: 09 Aug '17