Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells

Background: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers. Aim: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents. Methods: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays. Results: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 µM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 µM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs. Conclusion: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.

Nutritional inter-dependencies and a carbazole-dioxygenase are key elements of a bacterial consortium relying on a Sphingomonas for the degradation of the fungicide thiabendazole

BackgroundThiabendazole (TBZ), is a benzimidazole fungicide and anthelminthic whose high persistence and toxicity pose a serious environmental threat. In our quest for environmental mitigation we previously isolated the first TBZ-degrading bacterial consortium and provided preliminary evidence for its composition and the degrading role of a Sphingomonas. Here, we employed a multi-omic approach combined with DNA-stable isotope probing (SIP) to determine the genetic make-up of the key consortium members, to disentangle nutritional and metabolic interdependencies, to identify the transformation pathway of TBZ and to understand the genetic network driving its transformation.ResultsTime-series SIP in combination with amplicon sequencing analysis verified the key role of Sphingomonas in TBZ degradation by assimilating over 80% of the 13C-labelled phenyl moiety of TBZ. Non-target mass spectroscopy (MS) analysis showed the accumulation of thiazole-4-carboxamidine as a single dead-end transformation product and no phenyl-containing derivative, in line with the phenyl moiety assimilation in the SIP analysis. Time series metagenomic analysis of the consortium supplemented with TBZ or succinate led to the assembly of 18 metagenome-assembled genomes (MAGs) with >80% completeness, six (Sphingomonas 3X21F, γ-Proteobacterium 34A, Bradyrhizobiaceae 9B and Hydrogenophaga 19A, 13A, and 23F) being dominant. Meta-transcriptomic and -proteomic analysis suggested that Sphingomonas mobilize a carbazole dioxygenase (car) operon during the initial cleavage of TBZ to thiazole-4-carboxamidine and catechol, the latter is further transformed by enzymes encoded in a catechol ortho-cleavage (cat) operon; both operons being up-regulated during TBZ degradation. Computational docking analysis of the terminal oxygenase component of car, CarAa, showed high affinity to TBZ, comparable to carbazole, reinforcing its high potency for TBZ transformation. These results suggest no interactions between consortium members in TBZ transformation, performed solely by Sphingomonas. In contrast, gene expression network analysis revealed strong interactions between Sphingomonas MAG 3X12F and Hydrogenophaga MAG 23F, with Hydrogenophaga activating its cobalamin biosynthetic pathway and Sphingomonas its cobalamin salvage pathway along TBZ degradation.ConclusionsOur findings suggest interactions between consortium members which align with the “black queen hypothesis”: Sphingomonas detoxifies TBZ, releasing consortium members by a toxicant; in return for this, Hydrogenophaga 23F provides cobalamin to the auxotrophic Sphingomonas.

Isolation of the novel example of a monomeric organotellurinic acid

The synthesis of the first example of a monomeric, stable organotellurinic acid is reported by utilizing the σ-hole participation of the Te atom with the N atom of the 2-(2′-pyridyl)phenyl moiety.

Structural studies on dihydropyrimidine derivatives as Mycobacterium tuberculosis coenzyme-A carboxylase inhibitors

A dihydropyrimidine (DHPM) derivative was synthesized, characterized by X-ray diffraction and searched in silico for its inhibitory activities against AccD5 enzyme, the CT domain of a Mycobacterium tuberculosis ACCase. Its molecular structure was compared to another DHPM derivative (DHPM II). The results have shown that the (±)2,6-methano-4-thioxo-3,4,5,6-tetrahydro-2H-[1,3,5] benzoxadiazocines (DHPM I) and (±)2,6-methano-4-oxo-3,4,5,6-tetrahydro-2H-[1,3,5] benzoxadiazocines (DHPM II) belong to the monoclinic and triclinic systems, respectively, and their crystal structures are stabilized by N–H⋯O, O–H⋯O and N–H⋯S interactions. The DHPM derivatives established hydrogen bond interactions with the oxyanion-stabilizing residues (Gly-434/Ala-435) beyond the Thr-217, Phe-394 and Ile-216 in the biotin pocket. The predicted MoB of the DHPM derivatives (21R, 24S, 22R) configuration showed that its phenyl moiety was positioned on the interface between the biotin and propionyl-CoA pockets, suggesting a possible blockade of both subsites. Additionally, the hydrogen bonds involving the O-bridged phenyl ring of the DHPM derivatives (21S, 24R, 22S) configuration with Gly434 in the oxyanion-stabilizing region placed its phenyl moiety in the bottom of the biotin pocket establishing hydrophobic interactions with Leu164, Tyr167, Val459 and Ala155. These results indicate the DHPM derivatives as potential AccD5 inhibitors and promising starting points for future optimizations. Although the overlap of DHPM I and DHPM II did not present significant differences, the exchange of a sulfur atom for an oxygen atom increased the predicted biological potential.

New Quinoline Based Sulfonamide Derivatives: Cytotoxic and Apoptotic Activity Evaluation Against Pancreatic Cancer Cells

Background: Quinoline is a privileged scaffold especially known with antimalarial and antibacterial drugs before, presently followed anticancer efficiency with a new group of protein kinase inhibitors. Objective: In this work, combining quinoline ring, hydrazone and sulphonamide groups, we have synthesized N'-arylidene-2-[4-(quinolin-8-ylsulfonyl)piperazin-1-yl]acetohydrazide derivatives (3a-o) and evaluated their in vitro anticancer activity against cancerous cell lines PANC-1, CAPAN-1, and healthy cell line hTERT-HPNE. Method: Fifteen compounds were synthesized a simple, well-known three-step synthetic procedure starting from 8-quinolinesulfonylchloride. Cytotoxicity studies were performed according to the conventional MTT method. As a second stage, flow cytometric analysis was done to the nine most cytotoxic compounds for determining the mechanism of action which could be apoptosis and/or necrosis. </P><P> Results/Conclusion: According to anticancer activity evaluation, compound 3b bearing 4-methyl phenyl moiety exhibited significant cytotoxicity which has an IC50 value nearly four-fold lower than cisplatin displayed, whereas compound 3f bearing 4-trifluoromethyl phenyl moiety showed two-fold potency of the standard drug against PANC-1 cell line. Compounds 3h, 3k and 3n against CAPAN-1 also showed significant cytotoxicity, selectively. The most active compounds 3b, 3c, 3d, 3f, 3g, 3h, 3k and 3n against PANC-1 and compounds 3f, 3g, 3h, 3k and 3n against CAPAN-1 were selected to be studied in flow cytometry. Compound 3b induced apoptosis of PANC-1 cells with a percentage of 16.0%, whereas compound 3h induced apoptosis of CAPAN-1 cells with a value of 20.6%.