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Tailor N.K.,Jaypee University of Information Technology | Boon H.L.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
European Journal of Medicinal Chemistry | Year: 2013

The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22β-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG-MID) value of compound 3 (MG-MID -5.69) was higher than standard drug cisplatin (MG-MID -5.66) while comparable in case of compound 12 (MG-MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC ≥ 0.60). © 2013 Elsevier Inc. All rights reserved. Source


Monika,Jaypee University of Information Technology | Sharma A.,Jaypee University of Information Technology | Suthar S.K.,Jaypee University of Information Technology | Aggarwal V.,Jaypee University of Information Technology | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ. © 2014 Elsevier Ltd. All rights reserved. Source


Suthar S.K.,Jaypee University of Information Technology | Lee H.B.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
RSC Advances | Year: 2014

The ester conjugates of potent nuclear factor-kappa B (NF-κB) inhibitors with cyclooxygenase (COX) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) present a novel approach towards cancer treatment. The ester prodrugs of pentacyclic triterpenoid 3β,22β-dihydroxy-olean-12-en-28- oic acid (4) with different NSAIDs were synthesized for the dual inhibition of NF-κB and COX-2. The results indicated that the lead compound 14 suppressed the tumor necrosis factor-alpha-induced (TNF-α-induced) activation of NF-κB by inhibiting the inhibitor of the nuclear factor-kappa B kinase (IKK) activation, the inhibitor of the nuclear factor-kappa B alpha (IκBα) degradation and at the same time, it down-regulated the NF-κB mediated protein expression of COX-2 and cyclin D1. Furthermore, compound 14 inhibited lung adenocarcinoma A549 cell proliferation in a dose dependent manner and was found to be 50 folds more active than cisplatin in terms of IC50. Compound 14 was also found to be stable in an acidic pH, while it hydrolyzed readily in human plasma to release the active promoieties. From the results it can be inferred that the lantadene-NSAID prodrugs are promising anticancer candidates against lung cancer with a dual inhibition capability against both NF-κB and COX-2. © the Partner Organisations 2014. Source


Suthar S.K.,Jaypee University of Information Technology | Boon H.L.,Cancer Research Initiative Foundation | Sharma M.,Jaypee University of Information Technology
European Journal of Medicinal Chemistry | Year: 2014

The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties. © 2013 Elsevier B.V. All rights reserved. Source


Suthar S.K.,Jaypee University of Information Technology | Sharma N.,BAHRA University | Lee H.B.,Cancer Research Initiative Foundation | Nongalleima K.,Institute of Bioresources and Sustainable Development IBSD | Sharma M.,Jaypee University of Information Technology
Current Topics in Medicinal Chemistry | Year: 2014

The activation of transcription factors nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX-2) is critical in cancer; they act synergistically in promoting tumor growth, survival, and resistance to chemotherapy. Thus, combined targeting of NF-κB and COX-2 present an opportunity for synergistic anticancer efficacy. The ester prodrugs of pentacyclic triterpenoids reduced lantadene A (3), B (4), and its congener 22β-hydroxyoleanonic acid (5) with various non steroidal anti-inflammatory drugs (NSAIDs) present a novel approach. The ester prodrugs of 3 and 4 with diclofenac showed promising dual inhibition of NF-κB and COX-2. The lead prodrugs 14 and 15 exhibited inhibition of inhibitor of nuclear factor-kappa B kinaseβ (IKKβ) in the single-digit micromolar range and at the same time, prodrugs 14 and 15 showed marked cytotoxicity against A549 lung cancer cell line with IC50s 0.15 and 0.42 μM, respectively. The prodrugs 14 and 15 exhibited stability in the acidic pH and were hydrolyzed readily in the human blood plasma to release the active parent moieties. Thus, we have synthesized novel hybrid compounds to target both NF-κB and COX-2 via a prodrug approach, leading to promising anticancer candidates. © 2014 Bentham Science Publishers. Source

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