Medicinal Chemistry Research最新文献

Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids 6a, 6c, 6i, and 6j displayed the best response, with IC₅₀ values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids 6a, 6c, 6i, and 6j. Altogether, novel hybrids of monastrol-MLT, in particular, 6a (-H), 6c (3-OMe), 6i (3,4-OMe), and 6j (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.

The alcalase digestate of farmed Chinese giant salamander meat powder (FCGSMP) demonstrated antihypertensive properties through inhibition of angiotensin-I-converting enzyme (ACE), with an ACE IC₅₀ value of 22.8 ± 1.8 µg/mL. Initiated by a zwitterionic hydrophilic interaction liquid chromatography solid-phase extraction (ZIC HILIC-SPE) fractionation, FCGSMP alcalase hydrolysate was fractionated, and fraction H1 from the ZIC HILIC-SPE fractionation showed the highest angiotensin-I-converting enzyme inhibitory (ACEI) activity (ACE IC₅₀ = 21.3 ± 0.2 µg/mL). Fraction H1 from the ZIC HILIC-SPE fractionation was further separated using a reversed-phase C₁₈ solid-phase extraction (RP-SPE). Fraction S2 from the RP-SPE fractionation exhibited the highest ACEI activity (ACE IC₅₀ = 7.7 ± 0.2 µg/mL) among the six RP-SPE fractions. Using synthetic peptides, twenty identified peptides from fraction S2 were confirmed to have ACEI activity. The ACE IC₅₀ values of the four most potent ACEI peptides (LLPGW, PLYE, KLW, and LGEW) were calculated to be 9.1 ± 0.1, 67.2 ± 1.5, 92.5 ± 2.9, and 98.2 ± 4.7 µM, respectively. LLGPW (LW5) exhibited the strongest ACEI activity compared to the others. Furthermore, the study of its inhibitory mechanism using the Lineweaver-Burk plot suggested that LW5 acts as a competitive inhibitor. Molecular docking simulation of LW5 with human tACE (1O8A.pdb) indicated that LW5 can form interactions with the ACE catalytic site. Subsequently, LW5 was categorized as an ACE true-inhibitor type and remained unaltered during simulated gastrointestinal digestion. To the best of our knowledge, this is the first report of exploration into angiotensin-I-converting enzyme inhibitory peptides derived from farmed Chinese giant salamander meat.

Botulinum neurotoxins are the most lethal and category ‘A’ bioterrorism agent. Despite all efforts, there is no drug available for intoxicating human. The 8-HQ is a well-known privileged scaffold which possesses metal chelation properties and its derived compounds are reported to inhibit the catalytic activity of BoNTs. Novel derivatives of NSC1012 were designed and synthesized via Mannich reaction. After characterization by NMR & mass spectrometry, compounds were studied for its toxicity profiling by in vitro and in vivo experiments. The designed compounds were screened and validated against BoNTs using molecular docking and FTS assay. The derived derivatives displayed no significant hemolytic activity (upto 500 µM) and low cytotoxicity with the CC₅₀ value ranging from 105.94–80.97 µM. The in vivo assay reveals, 25 mM concentration is a NOAEL dose with no observed significant difference in biochemical parameters between the control and treated groups. Molecular docking study showed “hits” with the binding energies for BoNT/A found in the range of −11.65 to −7.24 kcal/mol, BoNT/B between −10.69 to −6.91 kcal/mol, BoNT/E it was −8.18 to −5.30 kcal/mol and for BoNT/F were −8.94 to −6.86 kcal/mol. The FTSA result reveals the binding efficiency of the compounds with the shift in ΔT_m from 8.10 to −7.15 °C for serotypes under study. Synthesized compounds are less toxic to the cells, not significantly affect the biochemical profile of the animals, and have shown high binding affinity as well as inhibited the catalytic activity of the BoNTs. These molecules can pave the way for the development of therapeutics against the neurotoxins.

The glyoxalase system, inherent in mammalian cells, serves as a natural detoxification mechanism that regulates cytotoxic byproducts, especially methylglyoxal (MG). Consisting of glyoxalase I (Glo-I), glyoxalase II (Glo-II), and glutathione (GSH), this system plays a vital role in managing these harmful substances. Glo-I catalyzes the rate-limiting step in MG detoxification and is found to be overexpressed in different cancer types, rendering it a promising target for novel anticancer drugs. In a previous study, a series of diazenylbenzenesulfonamide derivatives were synthesized and evaluated for their activity against Glo-I. Among these compounds, HA1, A1, and HA2 were identified as Glo-I inhibitors with IC₅₀ values of 1.36 ± 0.09, 1.36 ± 0.01, and 1.22 ± 0.07 µM, respectively, and were subsequently chosen as lead compounds for further investigation. In the present study, the lead compounds were subjected to structural optimization to develop more potent inhibitors. Various derivatives with distinct chemical features were synthesized and tested in vitro against Glo-I to establish their structure-activity relationship and determine the key interactions within the enzyme’s active site. Several compounds exhibited potent inhibitory activity with sub-micromolar IC₅₀ values. Notably, compound (E)-8-hydroxy-5-((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)diazenyl)quinoline-2-carboxylic acid (B9) emerged as the most potent compound, with IC₅₀ value of 0.44 ± 0.06 µM. The structure-activity relationship analysis of compound B9 underscored the significance of the 8-hydroxyquinoline moiety as well as the sulfathiazole moiety for its inhibitory activity. To gain deeper insights into the binding modes of the compounds within the enzyme’s active site, molecular docking studies were conducted, providing enhanced and accurate predictions.

Poly(ADP-ribose)polymerases (PARPs) have emerged as promising targets for the treatment of diseases, particularly in cancers, due to their significant biological functions involved in DNA damage. As a result, researchers worldwide have made substantial advances in this field. However, studies have revealed that PARPs inhibitors lack selectivity due to the conserved domain, limiting their clinical applications and emphasizing the need for selective inhibitors. In this perspective, we summarize the recent advancements in PARPs inhibitors, with a focus on selective inhibitors among PARP family. We discuss the designed strategy, structure-activity relationships, and crystal structure, while explaining the underlying mechanisms of selectivity, hoping to provide insights for the design of next generation of PARPs selective inhibitors.

Cyclin-dependent kinases (CDKs) play a major role in regulating transitions within the cell cycle. Given the roles of CDK4/6 in promoting oncogenesis, selective inhibition of CDK4/6 has emerged as a novel approach for the treatment of breast cancer and various other tumors. While first and second generation CDK4/6 inhibitors were instrumental in targeting cell cycle pathways, they had numerous drawbacks such as limited selectivity and off-target effects. For that reason, a third generation of inhibitors was introduced and provided improved selectivity towards CDK4/6 leading to fewer side effects. To date, four compounds have been approved by the FDA as selective inhibitors of CDK4/6: palbociclib, ribociclib, abemaciclib, and trilaciclib. In this mini review, we summarize the biological, clinical, and chemical aspects of trilaciclib, a first-in-class CDK4/6 inhibitor notable for its dual role in cell cycle regulation and myelopreservation. Trilaciclib was granted FDA approval on February 2021, to improve the outcome of patients with metastatic-stage small cell lung cancer (SCLC) by protecting bone marrow suppression during chemotherapy.