A promising approach in the development of potent anticancer agents is the utilization of a single molecule to target multiple malignancy features, such as angiogenesis, proliferation, and metastasis. Ruthenium metal complexation of bioactive scaffolds is documented to improve their biological activity. We assess the effects of Ru chelation on the anticancer properties of two bioactive flavones (1 and 2). In an endothelial cell tube formation assay, Ru complexes (1Ru and 2Ru) diminished the antiangiogenic properties inherent in their parent molecules. 1Ru, incorporating a 4-oxoflavone structure, effectively reduced the proliferation and migration of MCF-7 breast cancer cells (IC50 = 6.615 μM and 50% migration inhibition, p<0.01 at 1 μM). The cytotoxic activity of 4-thioflavone (2) on MCF-7 and MDA-MB-231 cell lines was attenuated by 2Ru, but 2Ru displayed a substantial increase in the inhibition of 2's migration, significantly in MDA-MB-231 cells (p < 0.05). Derivatives of the test samples demonstrated a non-intercalative interaction with VEGF and c-myc i-motif DNA sequences.
Inhibiting myostatin represents a compelling therapeutic strategy for the treatment of muscular atrophic diseases, a category encompassing conditions like muscular dystrophy. Myostatin inhibition was achieved by creating functionalized peptides, which were synthesized by the conjugation of a 16-mer myostatin-binding d-peptide to a photooxygenation catalyst. Myostatin-selective photooxygenation and inactivation of the peptides occurred under near-infrared irradiation, accompanied by a lack of significant cytotoxicity or phototoxicity. Because of their d-peptide chains, the peptides are impervious to enzymatic breakdown. The in vivo use of photooxygenation-based myostatin inactivation strategies is facilitated by these properties.
Chemotherapeutic efficacy is reduced as Aldo-keto reductase 1C3 (AKR1C3) facilitates the conversion of androstenedione to testosterone. Inhibition of AKR1C3, a target in breast and prostate cancer, could function as an effective adjuvant therapy for leukemia and other cancers. We screened steroidal bile acid fused tetrazoles in this study to determine their inhibitory effect on AKR1C3. Four C24 bile acids containing C-ring-fused tetrazoles displayed moderate to strong inhibition of AKR1C3 (37-88% reduction), whereas B-ring fused tetrazoles had no influence on AKR1C3 activity. In yeast cells, these four compounds, when assessed using a fluorescence-based assay, displayed no interaction with estrogen or androgen receptors, indicating a lack of estrogenic or androgenic activity. A prominent inhibitor exhibited a marked preference for AKR1C3 over AKR1C2, effectively inhibiting AKR1C3 with a half-maximal inhibitory concentration of 7 micromolar. Using X-ray crystallography at a 14 Å resolution, the structural determination of AKR1C3NADP+ in complex with this C-ring fused bile acid tetrazole was achieved. The results demonstrated that the C24 carboxylate is situated at the catalytic oxyanion site (H117, Y55). The tetrazole, in turn, interacts with tryptophan (W227), important in the recognition of steroids. BI-D1870 Molecular docking experiments suggest that the four most potent AKR1C3 inhibitors share strikingly similar binding configurations, hinting at the possibility that C-ring bile acid-fused tetrazoles constitute a new class of inhibitors for AKR1C3.
The protein cross-linking and G-protein activity of human tissue transglutaminase 2 (hTG2), a multifaceted enzyme, can lead to disease progression, including fibrosis and cancer stem cell propagation when dysregulated. This has driven the pursuit of small molecule, targeted covalent inhibitors (TCIs), with a crucial electrophilic 'warhead', to intervene in these pathogenic processes. Despite the considerable advancement in recent years of the range of warheads for TCI design, there has been little progress in the study of warhead function in hTG2 inhibitors. A structure-activity relationship study, utilizing rational design and synthesis, systematically varies the warhead of a previously reported small molecule inhibitor scaffold. Rigorous kinetic evaluation determines the effect on inhibitory efficiency, selectivity, and pharmacokinetic stability. Variations in warhead structure demonstrably affect the kinetic parameters k(inact) and K(I), highlighting the warhead's pivotal role in reactivity, binding affinity, and, consequently, isozyme selectivity. The structure of the warhead affects its stability within a living organism, which we model by assessing its inherent reactivity with glutathione, as well as its stability within hepatocytes and whole blood, to understand degradation pathways and the relative therapeutic efficacy of different functional groups. This study's contribution lies in the fundamental structural and reactivity information, highlighting the necessity of strategically designed warheads for the development of robust hTG2 inhibitors.
Upon aflatoxin contamination of developing cottonseed, the kojic acid dimer (KAD) metabolite is subsequently derived. KAD's greenish-yellow fluorescence is evident, but its biological activity has not yet been thoroughly investigated. This study demonstrates a four-step chemical synthesis, originating from kojic acid, for the large-scale preparation of KAD, achieving approximately 25% overall yield. Single-crystal X-ray diffraction verified the KAD's structure. Across a range of cell types, the KAD demonstrated good safety parameters, and a noteworthy protective outcome was seen in SH-SY5Y cells. At concentrations of less than 50 molar, KAD's efficacy in scavenging ABTS+ free radicals surpassed that of vitamin C in an assay; the resistance of KAD to H2O2-induced reactive oxygen species was confirmed using both fluorescence microscopy and flow cytometry. The KAD's contribution to superoxide dismutase activity enhancement is apparent, and this is potentially the mechanism behind its antioxidant properties. The KAD's moderate suppression of amyloid-(A) deposition was further distinguished by its selective chelation of Cu2+, Zn2+, Fe2+, Fe3+, and Al3+, trace metals linked to Alzheimer's disease progression. Given its effectiveness in counteracting oxidative stress, promoting neuroprotection, reducing amyloid plaque formation, and managing metal accumulation, the KAD compound holds promise as a multi-target therapy for Alzheimer's disease.
21-membered cyclodepsipeptides, known as nannocystins, are a family possessing excellent anticancer activity. Nevertheless, the macrocyclic framework of these molecules presents a substantial hurdle to structural alteration. By implementing post-macrocyclization diversification, this issue is addressed. For particular consideration, a novel serine-incorporating nannocystin was constructed, facilitating its appended hydroxyl group's versatility in producing numerous variations of side chain analogs. The considerable effort performed not only advanced the structure-activity relationship studies in the intended subdomain, but also resulted in the development of a macrocyclic coumarin-labeled fluorescent reporter. The probe exhibited good cell permeability, as evidenced by uptake experiments, with the endoplasmic reticulum being identified as its specific subcellular site.
Pharmaceutical small molecules, containing the cyano functional group, number more than 60, demonstrating the broad applications of nitriles in medicinal chemistry. Pharmacokinetic profiles of drug candidates are often enhanced by nitriles, in addition to their substantial involvement in noncovalent interactions with macromolecular targets. Furthermore, the cyano group serves as an electrophilic reagent, enabling the covalent attachment of an inhibitor to a desired target, creating a stable covalent adduct. This approach often surpasses the effectiveness of non-covalent inhibitors. The approach has attracted considerable notoriety in recent years, especially in its application to diabetes and drugs approved for COVID-19. BI-D1870 Despite the primary role of nitriles as reactive centers in covalent ligands, their application extends to converting irreversible inhibitors to reversible forms, a noteworthy strategy for both kinase inhibition and protein breakdown. This review delves into the cyano group's contributions to covalent inhibitors, including strategies for manipulating its reactivity, and the feasibility of achieving selectivity solely via warhead modification. Concluding, we detail the overview of nitrile-containing covalent compounds, including their presence in approved drugs and newly documented inhibitors.
Similar pharmacophoric features characterize both BM212, a potent anti-TB agent, and the antidepressant sertraline. The identification of several CNS drugs with appreciable Tanimoto scores arose from shape-based virtual screening of the BM212 target in the DrugBank database. The simulations of the docking process also confirmed the preferential binding of BM212 to the serotonin reuptake transporter protein (SERT), exhibiting a docking score of -651 kcal/mol. Using available SAR data on sertraline and other antidepressants, we meticulously designed, synthesized, and evaluated twelve 1-(15-bis(4-substituted phenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamines (SA-1 through SA-12) for their in vitro serotonin transporter (SERT) inhibitory potential and subsequent in vivo antidepressant effects. The compounds underwent in vitro screening for 5HT reuptake inhibition, utilizing the platelet model as a system. 1-(15-bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)-N-methylmethanamine, one of the tested compounds, showed a serotonin uptake inhibition identical to that of sertraline, both registering an absorbance of 0.22. BI-D1870 The compound BM212 had an impact on 5-HT uptake, however its influence was weaker relative to the standard absorbance of 0671. In addition, SA-5 was scrutinized for its in vivo antidepressant efficacy using the chronic unpredictable mild stress paradigm to induce depressive states in mice. To gauge the impact of BM212 and SA-5 on animal behavior, a comparative study was conducted, evaluating the findings alongside the well-established effects of sertraline.