Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi-Zhu Reaction and In Vitro-In Silico Studies against Breast Carcinoma.

An Ugi-Zhu three-component reaction (UZ-3CR) coupled in a one-pot manner to a cascade process (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of pyrrolo[3,4-b]pyridin-5-ones in 20% to 92% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against breast cancer cell lines MDA-MB-231 and MCF-7, finding that compound 1f, at a concentration of 6.25 µM, exhibited a potential cytotoxic effect. Then, to understand the interactions between synthesized compounds and the main proteins related to the cancer cell lines, docking studies were performed on the serine/threonine kinase 1 (AKT1) and Orexetine type 2 receptor (Ox2R), finding moderate to strong binding energies, which matched accurately with the in vitro results. Additionally, molecular dynamics were performed between proteins related to the studied cell lines and the three best ligands.

Flavonoids as regulators of TIMPs expression in cancer: Consequences, opportunities, and challenges.

Cancer is one of the leading causes of death in patients worldwide, where invasion and metastasis are directly responsible for this statement. Although cancer therapy has progressed in recent years, current therapeutic approaches are ineffective due to toxicity and chemoresistance. Therefore, it is essential to evaluate other treatment options, and natural products are a promising alternative as they show antitumor properties in different study models. This review describes the regulation of tissue inhibitors of metalloproteinases (TIMPs) expression and the role of flavonoids as molecules with the antitumor activity that targets TIMPs therapeutically. These inhibitors regulate tissue extracellular matrix (ECM) turnover; they inhibit matrix metalloproteinases (MMPs), cell migration, invasion, and angiogenesis and induce apoptosis in tumor cells. Data obtained in cell lines and in vivo models suggest that flavonoids are chemopreventive and cytotoxic against various types of cancer through several mechanisms. Flavonoids also regulate crucial signaling pathways such as focal adhesion kinase (FAK), phosphatidylinositol-3-kinase (PI3K)-Akt, signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NFκB), and mitogen-activated protein kinase (MAPK) involved in cancer cell migration, invasion, and metastasis. All these data reposition flavonoids as excellent candidates for use in cancer therapy.

Brazilin: Biological activities and therapeutic potential in chronic degenerative diseases and cancer.

Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.