Dammarane triterpenoids are affordable and bioactive natural metabolites with great structural potential, which makes them attractive sources for drug development. The aim of the study was to investigate the potency of new dipterocarpol derivatives for the treatment of diabetes. Two dammaranes (dipterocarpol and its 20(24)-diene derivative) were modified by a Claisen-Schmidt aldol condensation to afford C2(E)-arylidenes in good yields. The majority of the synthesized compounds exhibited an excellent-to-moderate inhibitory effect toward α-glucosidase (from S. saccharomyces), among them eight compounds showed IC50 values less than 10 μM. 3-Oxo-dammarane-2(E)-benzylidenes (holding p-hydroxy- 3 l and p-carbonyl- 3 m substituents) demonstrated the most potent α-glucosidase inhibition with IC50 0.753 and 0.204 μM, being 232- and 857-times more active than acarbose (IC50 174.90 μM), and a high level of NO inhibition in Raw 264.7 cells with IC50 of 1.75 and 4.57 μM, respectively. An in vivo testing of compound 3 m (in a dose of 20 mg/kg) on a model of streptozotocin-induced T1DM in rats showed a pronounced hypoglycemic activity, the ability to reduce effectively the processes of lipid peroxidation in liver tissue and decrease the excretion of glucose and pyruvic acid in the urine. Compound 3 m reduced the death of diabetic rats and preserved their motor activity.

Background: The adverse effects of anti-inflammatory drugs urges the search for new anti-inflammatory agents. This study aims at the preclinical analysis of the in-house synthesized small molecule IPX-18. Human whole blood (HWB), peripheral blood mononuclear cells (PBMCs), and neutrophils were used. Rat basophil cells (RBL-2H3) were used to assess degranulation. Binding stability to NF-κB-p50 was predicted using computational docking and molecular dynamic simulations. Essential signaling proteins were evaluated through flow cytometry. Results: IPX-18 inhibited the release of TNF-α with an IC50 value of 298.8 nM and 96.29 nM in the HWB and PBMCs, respectively. The compound depicted an IC50 value of 217.6 nM in the HWB and of 103.7 nM in the PBMCs for IFN-γ inhibition. IL-2 release and IL-8 release were inhibited by IPX-18 in the HWB and PBMCs. The compound controlled the migration of and the elastase in the activated neutrophils. The IC50 value for basophil activation through the FcεRI receptor assay was found to be 91.63 nM. IPX-18 inhibited RBL-2H3-degranulation with an IC50 value of 98.52 nM. The computational docking analysis predicted that IPX-18 would effectively bind NF-κB-p50. NF-κB-phosphorylation in the activated RBL-2H3 cells was decreased, and the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were increased with IPX-18 treatment. Conclusions: IPX-18 demonstrated efficacy in mediating the effector cells\' inflammatory responses through NF-κB/Nrf2 signaling.

The chemical transformation of the tricyclic furo[2,3-d]pyrimidines was performed under isosteric and scaffold-hopping strategies focusing on the synthesis of its arylidene and imine-containing derivatives. Naturally-occurring alkaloids mackinazolinone and isaindigotone were as templates of target heterocycles. Synthesized compounds evaluated for their antitumor activity on human cancer cervical HeLa, breast MCF-7, and colon HT-29 cell lines. Four compounds: 8c, 8e, 10b, and 10c demonstrated potency against HeLa and HT-29 cell lines, and IC50 values were between 7.37-13.72 μM, respectively. The molecular docking results showed that compounds 8c and 10b had good binding and high matching with the target EGFR protein.

A series of 24-ethylcholest-4-ene-3,6-dione 2E-arylidene-derivatives has been synthesized by a Claisen-Schmidt reaction from a natural phytosterol β-sitosterol with yields of 80-85%. The structure of the obtained compounds was confirmed by NMR spectroscopy, including two-dimensional correlation experiments. The synthesized compounds were evaluated for their in vitro cytotoxicity and α-glucosidase inhibitory activity. It was established that compound 3 with pyridin-3-ylmethylene moiety exhibited a selective cytotoxic effect against the U251 cancer cell line with 99.31% inhibition of cancer cell growth. Compounds with pyridin-4-ylmethylene 4 and furan-2-ylmethylene-5 fragments were the most active inhibitors of α-glucosidase with IC50 64.00 and 38.95 µM, being 3- and 5-times more active than acarbose. Binding mode to α-glucosidase and ADMET characteristics for the lead molecule 5 were proposed computationally. To sum up, an efficient approach to the derivatives with promising antidiabetic activity based on available natural product β-sitosterol is suggested.

The use of natural compounds as starting point for semisynthetic derivatives has already been proven as a valuable source of active anticancer agents. Hollongdione (4,4,8,14-tetramethyl-18-norpregnan-3,20-dion), obtained by few steps from dammarane type triterpenoid dipterocarpol, was chemically modified at C2 and C21 carbon atoms by the Claisen-Schmidt aldol condensation to give a series of arylidene derivatives. The anticancer activity of the obtained compounds was assessed on NCI-60 cancer cell panel, revealing strong antiproliferative effects against a large variety of cancer cells. 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 emerged as the most active derivative as indicated by its GI50 values in the micromolar range which, combined with its high selectivity index values, indicated its suitability for deeper biological investigation. The mechanisms involved in compound 9 antiproliferative activity, were investigated through in vitro (DAPI staining) and ex vivo (CAM assay) tests, which exhibited its apoptotic and antiangiogenic activities. In addition, compound 9 showed an overall inhibition of mitochondrial respiration. rtPCR analysis identified the more intimate activity at pro-survival/pro-apoptotic gene level. Collectively, the hollongdione derivative stand as a promising therapeutic option against melanoma and breast cancer provided that future in vivo analysis will certify its clinical efficacy.

A series of novel hybrid chalcone N-ethyl-piperazinyl amide derivatives of oleanonic and ursonic acids were synthesized, and their cytotoxic potential was evaluated in vitro against the NCI-60 cancer cell line panel. Compounds 4 and 6 exhibited the highest overall anticancer activity, with GI50 values in some cases reaching nanomolar values. Thus, the two compounds were further assessed in detail in order to identify a possible apoptosis- and antiangiogenic-based mechanism of action induced by the assessed compounds. DAPI staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that up-regulation of pro-apoptotic Bak gene combined with the down-regulation of the pro-survival Bcl-XL and Bcl-2 genes caused altered ratios between the pro-apoptotic and anti-apoptotic proteins\' levels, leading to overall induced apoptosis. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, suggesting that compounds may induce apoptotic cell death through targeted anti-apoptotic protein inhibition, as well. Ex vivo determinations showed that both compounds did not significantly alter the angiogenesis process on the tested cell lines.

Rational combination of natural and synthetic derivatives to treat lung cancer has advantages of both efficacy and safety. Herein, the combination of indirubin-3-monoxime (I3M), a chemical derived from Chinese herbal medicine and FXY-1, a synthetic arylidene derivative, was tested for combined activity in lung cancer cells. A dose-dependent synergistic reduction in cell viability was recorded with the combinations in A549 and NCI-H460 cells. Combination treatments of I3M and FXY-1 showed antimetastatic effects in both cells. Cell cycle analysis revealed G1 growth phase reduction with subsequent accumulation of sub G0 contents. Annexin V assay revealed higher apoptotic cells with combinations compared to individual treatments. I3M + FXY-1 combination significantly decreased the antiapoptotic Bcl-2 protein and increased pro-apoptotic Bax protein levels. These results demonstrate efficacy of I3M + FXY-1 in lung cancer cells and suggest further preclinical research in animal models to develop it into a new form combination chemotherapeutic against lung cancer. PRACTICAL APPLICATIONS: Current investigation will open new options in rational combinations of natural and synthetic compounds to treat cancer. The observed efficacy and safety of the combinations will add to the advantage of higher therapeutic window in formulating treatment regimens. The antimetastatic effects by the combinations provides promising efficacy in controlling the lung cancer progression. A detailed in vivo investigation is recommended to transform the combinations to novel chemotherapeutic options against lung cancer.

OBJECTIVE: Human lung cancer is contributed to be a major mortality factor in the cancer-related deaths. Arylidene indan-ones constitute a new class of potential anti-tumor compounds. Herein, we report the biological efficacy of the 2-arylidene-4, 7-dimethyl indan-1-one (FXY-1), a potential lead molecule of arylidene indan-ones in lung cancer models. We previously described anticancer activity of FXY-1 against human breast adenocarcinoma.
METHODS: FXY-1 efficacy was assessed by standard anticancer screening in NCI-H 460, A549, NCI-H 1975 and NCI-H 2170 cells. Initial molecular docking analysis was performed to check the interaction of compound to Akt enzyme. Anti-proliferation, anti-metastatic and transendothelial cell migration were performed to check efficacy of the drug. Western blot analysis was performed to understand the regulation of pro-apoptotic and anti-apoptotic proteins by the compound. The effect of FXY-1 on caspase induction and Akt phosphorylation were checked using Western blot analysis. Flow cytometry was used to reveal the cell cycle changes and apoptosis-inducing properties of FXY-1 in the lung cancer cells. In-vitro Akt inhibition property of the compound was studied using a fluorescence-based, coupled-enzyme reaction. The in-vivo efficacy of the compound was determined using a mouse xenograft model.
RESULTS: Our molecular docking analysis reveals higher interaction of FXY-1 with Akt. FXY-1 depicted anti-proliferative and pro-apoptotic activity with higher therapeutic window in-vitro in NCI-H 460 and A549 cells. The compound treatment to lung cancer cells resulted in induction of DNA fragmentation, inhibition of transendothelial migration, caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage. FXY-1 treatment resulted in G 0/G 1 arrest in both cell lines at lower concentrations, but led to apoptosis at higher doses. Western blot analysis revealed dephosphorylation of Akt (Ser 473) with activation of p53, Bax, Bak, Bid and reduction in Bcl-2 and Bcl-xL levels. Further mechanistic investigation showed that FXY-1 activity was facilitated through an allosteric inhibition of Akt enzyme. FXY-1 treatment significantly reduced the tumor growth and pAkt levels in mouse xenograft exhibiting the in-vivo efficacy in the compound.
CONCLUSIONS: Collectively, our results suggest DNA damage-mediated activation by FXY-1 in lung cancer cells leading to extensive apoptosis through the mitochondrial pathway.