Triple-negative breast cancer (TNBC) remains as the deadliest cancer type due to the lack of treatment options. Hence, several attempts have been made to develop new anticancer for TNBC therapy. This study intended to challenge curcumin analog (CCA)-1.1, which is derived from pentagamavunone-1 structure, against the 4T1 cell line and TNBC cell model, covering the cytotoxic activity in correlation with cell cycle progression, apoptosis induction, reactive oxygen species (ROS) generation, and senescence evidence. The cell viability, cell cycle profile, apoptosis induction, intracellular ROS level, and senescence induction were determined in vitro using trypan blue exclusion, propidium iodide (PI) staining, Annexin-PI staining, dichlorofluorescein diacetate staining, and senescence-associated-β-gal method. CCA-1.1 showed cytotoxic activity on 4T1 cells, giving half maximal inhibitory concentration value of 3M, but was less toxic on non-cancerous 3T3-L1 cells. CCA-1.1 induced rapid cell death and inhibited cell cycle progression at the mitotic phase. Instead, of causing apoptosis, CCA-1.1 induced mitotic catastrophe. Furthermore, CCA-1.1 itself increased the intracellular ROS level and induced senescence, possibly through catastrophic cell death. Altogether, our preliminary study strengthens the potency of CCA-1.1 for its anticancer activities against TNBC cells and prospective to be pharmaceutically developed as a novel candidate for cancer therapy.

Curcumin-like structure (CCA-1.1) induces permanent mitotic arrest (Senescence) on Triple-negative breast cancer (TNBC) cells, 4T1

Among the post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, and a large set of functions, including DNA repair, transcription, and cell signaling, have been assigned to this post-translational modification (PTM). This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing monoADP-ribosylation/polyADP-ribosylation (MAR/PAR) cycling in cancers. Of note, there is potential for the application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, the suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control.

COVID-19 is affected in more than 200 countries in the world. In this article, some pyrazole bearing 9-anilinoacridines(1a-z) were designed by in-silico studies for SARS-CoV-2 Mpro inhibitory activity. The docking for 1a-z against SARS-CoV-2 Mpro (5R82.pdb) targeting corona virus using Schrodinger suit. The Glide module is used for docking, qikprop for in-silico ADMET screening and Prime MM-GB/SA to determine binding energy of ligands. From the results, many compounds are significantly binding with SARS-CoV-2 Mpro with high G-score when compared to one of the currently recommended drug for COVID19, Hydroxychloroquine (-5.47). From results, many compounds exhibited similar interactions with SARS-CoV-2 Mpro and the aminoacids between GLN19 and GLY143 plays major role for binding. The in-silico ADMET properties are within the recommended values. The MM-GBSA calculations for most of the potent inhibitors are stable. In conclusion, 1t,m,j,o are SARS-CoV-2 Mpro inhibitors and may be useful for significant COVID19 activity after further refinement.

COVID-19 Activity of Some 9-Anilinoacridines substituted with Pyrazole against SARS CoV2 Main Protease: An In-silico Approach

Modern cancer therapy now routinely employs the blocking of many oncoproteins or pathways. With two or more medicines, multiple inhibitions are often accomplished via DML techniques. In this study, we developed 30 quinazolinone derivatives as PARP1 and STAT3 dual inhibitors using DML methods and these compounds were tested for their dual inhibitory effect on PARP1 and STAT3 using docking, MM-GBSA, and molecular dynamics simulation investigations. The docking studies of ligands against PARP1 and STAT3 were performed using the Glide module, in silico ADMET screening was performed using the quickprob module, binding energy calculation was performed using the Prime MM-GBSA module, MD simulation was performed using the Desmond module, and atomic charges were calculated using the Jaguar module of Schrodinger suite 2019-4. Of the substances studied, the derivative 1f has a considerable gliding score. The in silico ADMET characteristics are within the approved range. PRIME MM-GB/SA was used to compute the binding free energy, and the results are substantial. To investigate the dynamic behavior of the protein-ligand complex, compound 1f was subjected to MD simulation at 100 ns. The tested chemical 1f produced the greatest results in MD simulations and MM-GBSA calculations, indicating that this ligand can inhibit more effectively.Communicated by Ramaswamy H. Sarma.

In-silico screening and molecular dynamics simulation of quinazolinone derivatives as PARP1 and STAT3 dual inhibitors: a novel DML approaches.

/pdf/design-synthesis-and-in-vitro-biological-evaluation-of-parp-2v0mlfa6.pdf

Design, Synthesis, and In-Vitro Biological Evaluation of PARP-1 Inhibitors Based on a 4-(Benzylideneamino)-N-(Quinolin-8-yl)Benzamide Scaffold

BACKGROUND 1,3,4-thiadiazolo pyrimidine is a lead molecule that is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. OBJECTIVE The objective of the study was to synthesize a series of 5-amino-7-(substituted aldehyde)-2[(naphthalene- 2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives and evaluate their possible in vitro and in vivo anticancer activity. METHODS Herein, we report the synthetic scheme, which was followed for the preparation of a series of title compounds B1- B9 outlined in scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo- 2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in the presence of phosphoryl chloride at a temperature of 65-75°C. The obtained compound reacted with malononitrile and an appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 - B9). The purity of the synthesized compounds was ensured by various spectral analyses. RESULTS In in silico molecular docking studies, compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer profile of compounds B1, B3, and B9 is significant when compared to the standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, and B7 are the most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies were carried out using DMBA induced model. CONCLUSION The in silico docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of PARP1 enzyme. In silico ADME properties of synthesized compounds were also studied and showed good drug-like properties.

1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors

Translational Chemotherapy for triple negative Breast Cancer - A Review on significance of poly (ADP-ribose) polymerase 1 (PARP 1) inhibitors

Causal and attribution studies are essential for earth scientific discoveries and critical for informing climate, ecology, and water policies. However, the current generation of methods needs to keep pace with the complexity of scientific and stakeholder challenges and data availability combined with the adequacy of data-driven methods. Unless carefully informed by physics, they run the risk of conflating correlation with causation or getting overwhelmed by estimation inaccuracies. Given that natural experiments, controlled trials, interventions, and counterfactual examinations are often impractical, information-theoretic methods have been developed and are being continually refined in the earth sciences. Here we show that transfer entropy-based causal graphs, which have recently become popular in the earth sciences with high-profile discoveries, can be spurious even when augmented with statistical significance. We develop a subsample-based ensemble approach for robust causality analysis. Simulated data, and observations in climate and ecohydrology, suggest the robustness and consistency of this approach.

pdf/robust-causality-and-false-attribution-in-data-driven-earth-2te14d0k.pdf

Robust Causality and False Attribution in Data-Driven Earth Science Discoveries

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1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors

Translational Chemotherapy for triple negative Breast Cancer - A Review on significance of poly (ADP-ribose) polymerase 1 (PARP 1) inhibitors

Robust Causality and False Attribution in Data-Driven Earth Science Discoveries