3‑Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

In an effort to develop new compounds for managing drug-induced liver injury, we prepared 23 novel hybrids based on 3-acetyl-11-keto-β-boswellic acid (AKBA) using various biocompatible linkers. A bioguided approach was employed to identify the most promising hybrid. Eight compounds exhibited superior anti-inflammatory activity compared to the parent compound. Two of these hybrids (5b and 18) were able to reduce gene expression of TNF-α in LPS-induced inflammation in RAW 264.7 cells, similar to dexamethasone. Subsequently, the hepatoprotective potential of these hybrids was evaluated against acetaminophen (APAP) toxicity in HepG2 cells at doses of 1 and 10 μM. Both hybrids effectively restored cytokine levels, which had been elevated by APAP, to normal levels. Furthermore, they normalized depleted superoxide dismutase and reduced glutathione levels while significantly reducing malondialdehyde (MDA) levels. Network pharmacology analysis suggested that AKBA-based hybrids exert their action by regulating PI3K and EGFR pathways, activating anti-inflammatory mechanisms, and initiating tissue repair and regeneration. Molecular docking studies provided insights into the interaction of the hybrids with PI3K. Additionally, the hybrids demonstrated good stability at different pH levels, following first-order kinetics, with relatively long half-lives, suggesting potential for absorption into circulation without significant degradation

New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres - Fig 9

<p>FT-IR spectrum of a) PLGA, b) Pure 7e, c) Physical mixture of the PLGA + 7e, d) Plain microspheres, and e) 7e-loaded microspheres.</p

Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors

As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a–c, 7a–c, and 8a–c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a–c), meta (7a–c), or para-positon (8a–c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a–c, 7b, and 8a–b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.</p

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells

<p>Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles <b>6a–p</b>, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles <b>6a</b>, <b>6e</b> and <b>6i</b> emerged as the most potent analogues with IC₅₀ = 6.70, 6.40 and 6.70 µM, respectively. Compounds <b>6a</b> and <b>6e</b> induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, <b>6e</b> displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles <b>6e</b> and <b>6i</b> displayed good inhibitory activity against EGFR (IC₅₀ = 120 and 150 nM, respectively). Collectively, these data demonstrated that <b>6e</b> might be a potential lead compound for the development of effective anti-TNBC agents.</p

IC₅₀ for reductions in the total cell number and cell cycle effects of compound 7e and sunitinib.

<p>IC₅₀ for reductions in the total cell number and cell cycle effects of compound 7e and sunitinib.</p

Chemical structures of some bioactive bis-isatin compounds.

<p>Chemical structures of some bioactive bis-isatin compounds.</p

A-549 human lung cancer cells were treated with 3.3 and 10 μM 7e over a time course from 2–48 h.

<p>Caspase 3/7 activity was measured by a luminescence-based homogenous assay.</p

Chemical structures of some clinically used isatine-based anticancer agents.

<p>Chemical structures of some clinically used isatine-based anticancer agents.</p

Particle size distribution of 7e-loaded PLGA microspheres.

<p>Particle size distribution of 7e-loaded PLGA microspheres.</p

Inhibitory concentration 50% (IC₅₀) of anti-proliferative activity of the selected compounds 7b, 7d, 7e and sunitinib against HT-29, ZR-75 and A-549 cell lines.

<p>Inhibitory concentration 50% (IC₅₀) of anti-proliferative activity of the selected compounds 7b, 7d, 7e and sunitinib against HT-29, ZR-75 and A-549 cell lines.</p