Current Issue : January-March Volume : 2022 Issue Number : 1 Articles : 5 Articles
To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure–activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2–C3, providing an avenue for achieving 3-O-carbamoyl-5,7,20-O-trimethylsilybins. The application of the synthetic method can be extended to the synthesis of 3-O-carbamoyl-3,4,5,7-O-tetramethyltaxifolins. The antiproliferative potency of 5,7,20-O-trimethylsilybin and its nine 3-carbamoyl derivatives were assessed in an ARpositive LNCaP prostate cancer cell line and two AR-null prostate cancer cell lines (PC-3 and DU145). Our preliminary bioassay data imply that 5,7,20-O-trimethylsilybin and four 3-O-carbamoyl- 5,7,20-O-trimethylsilybins emerge as very promising lead compounds due to the fact that they can selectively suppress AR-positive LNCaP cell proliferation. The IC50 values of these five 5,7,20-Otrimethylsilybins against the LNCaP cells fall into the range of 0.11–0.83 μM, which exhibit up to 660 times greater in vitro antiproliferative potency than silibinin. Our findings suggest that carbamoylated 5,7,20-O-trimethylsilybins could serve as a natural product-based scaffold for new antiandrogens for lethal castration-resistant prostate cancer....
Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment able to trigger the immune response. Structural modification of MDP can lead to the preparation of analogs with improved immunostimulant properties, including desmuramyl peptides (DMPs). The aim of this work was to prepare the desmuramyl peptide (L-Ala-D-Glu)-containing adamantyl-triazole moiety and its mannosylated derivative in order to study their immunomodulatory activities in vivo. The adjuvant activity of the prepared compounds was evaluated in a murine model using ovalbumin as an antigen, and compared to the reference adjuvant ManAdDMP. The results showed that the introduction of the lipophilic adamantyl-triazole moiety at the C-terminus of L-Ala-D-Glu contributes to the immunostimulant activity of DMP, and that mannosylation of DMP modified with adamantyl-triazole causes the amplification of its immunostimulant activity....
A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and evaluated on 60 human cancer cell lines according to protocols available at the National Cancer Institute (Bethesda, MD, USA). Some derivatives proved to be potent antiproliferative agents, showing GI50 values in the submicromolar range. Compound 5b emerged as the most active and was further studied in Jurkat cells in order to determine the effects on cell-cycle phases and the kind of cell death induced. Finally, oxidative stress and DNA damage induced by compound 5b were also analyzed....
A series of novel thiazolyl hydrazine derivatives 3a–3o were synthesized and evaluated for their in vitro antifungal activity against six phytopathogenic strains, namely, Botryosphaeria dothidea (B. d.), Gibberella sanbinetti (G. s.), Fusarium oxysporum (F. o.), Thanatephorus cucumeris (T. c.), Sclerotinia sclerotiorum (S. s.), and Verticillium dahliae (V. d.), by the classical mycelial growth rate method. Biological assessment results showed that most of these target compounds showed good antifungal activity toward tested strains. Especially, compound 3l showed excellent antifungal activities against B. d. and G. s. with relatively lower EC50 values of 0.59 and 0.69 μg/mL, respectively, which were extremely superior to those of commercial fungicides fluopyram, boscalid, and hymexazol and were comparable to those of carbendazim. Given the excellent bioactivity of designed compounds, this kind of thiazolyl hydrazine framework can provide a suitable point for exploring highly efficient antifungal agents....
A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate–good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 μM concentration showed that five of the compounds strongly inhibited growth and killed parasites....
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