Non-Covalent Interactions in the Self-Assembly of Dihydropyridone Supramolecules and In Vitro Anti-Cancer Assessment in Human Lung Adenocarcinoma Cell Line (A549).

The synthesis of dihydropyridone derivatives has been reported by ring rearrangement of pyrans using iodine and formic acid as a catalyst separately. Dihydropyridones were crystallized subjected for single-crystal X-ray crystallography to acquire their structural parameters. The different non-covalent interactions involved within the supramolecular systems were studied and validated using Hirshfeld surface plot analysis. N-H⋅⋅⋅O interactions between the lactam group dominate. Still, other non-covalent interactions such as C-H⋅⋅⋅N, C-H⋅⋅⋅O, C-H⋅⋅⋅C, N-H⋅⋅⋅N, C-H⋅⋅⋅π, and lone pair⋅⋅⋅π systems act as the driving force in facilitating the self-assembly of the dihydropyridone supramolecules. The synthesized compounds were analyzed by in vitro techniques using human lung adenocarcinoma (A549) to evaluate their cytotoxic activities. Ethyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,4,5,6- tetrahydropyridine-3-carboxylate has shown the highest cytotoxicity among all the synthesized compounds. Molecular recognition properties of the dihydropyridone compounds were also studied, employing molecular docking tools to gain insight into the binding mode inside the allosteric binding pocket of the Eg5 protein through non-covalent interactions.

Progressive plasticity during colorectal cancer metastasis.

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

[Waldenström's macroglobulinemia]. / Macroglobulinémie de Waldenström.

Waldenström's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.