ABSTRACT
Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade. It is hoped that 2-thiohydantoin S-arylidenes are worth further studies as biologically active compounds.
Subject(s)
Androgens/chemistry , Androgens/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Thiohydantoins/chemistry , Thiohydantoins/pharmacology , Allosteric Regulation/drug effects , Androgens/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Chemistry Techniques, Synthetic , HEK293 Cells , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Interaction Maps/drug effects , Proto-Oncogene Proteins c-mdm2/metabolism , Receptors, Androgen/metabolism , Thiohydantoins/chemical synthesis , Tumor Suppressor Protein p53/metabolismABSTRACT
Aging results in various deleterious changes in the human body that may lead to loss of function and the manifestation of chronic diseases. While diseases can generally be reliably diagnosed, the aging process itself requires more sophisticated approaches to evaluate its progression. Numerous attempts have been made to establish biomarkers to quantify human aging at the cellular, tissue, and organismal level. Here, an up-to-date overview of biomarkers related to human aging with an emphasis on biomarkers that take into account different mechanisms of aging between individuals is provided. Classical discrete molecular and non-molecular biomarkers handpicked by researches on the base of their strong correlation with age, as well as emerging omics-based biomarkers, are discussed and potential future directions and developments in the field of aging assessment are outlined.
Subject(s)
Aging , Animals , Biomarkers/analysis , Cellular Senescence , Computational Biology/methods , Genomic Instability , Humans , MutationABSTRACT
Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.
Subject(s)
Antigens, Surface/chemistry , Antineoplastic Agents/chemical synthesis , Doxorubicin/chemistry , Glutamate Carboxypeptidase II/chemistry , Animals , Antigens, Surface/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Nucleus/chemistry , Cell Nucleus/metabolism , Cell Survival/drug effects , Doxorubicin/pharmacology , Glutamate Carboxypeptidase II/metabolism , Humans , Ligands , Male , Mice , Molecular Docking Simulation , Prostatic Neoplasms/drug therapy , Protein Structure, Tertiary , Transplantation, HeterologousABSTRACT
A novel stereocontrolled assembly of spiro[oxindole-3,2'-pyrrolidines] via [3+2]-cycloaddition of donor-acceptor cyclopropanes to electron-poor ketimines, iminooxindoles, was developed. The method allows for efficient employment of common readily available donor-acceptor cyclopropanes, functionalized with ester, keto, nitro, cyano etc. groups, and N-unprotected iminooxindoles. The stereospecificity of the initial SN2-like imine attack on a cyclopropane molecule together with a high diastereoselectivity of further C-C bond formation facilitate a rapid access to spiro[oxindole-3,2'-pyrrolidines] in their optically active forms. Preliminary in vitro testing of the synthesized compounds against LNCaP (p53+) and PC-3 (p53-) cells revealed good antiproliferative activities and p53-selectivity indices for several compounds that are intriguing in terms of their further investigation as inhibitors of MDM2-p53 interaction.
Subject(s)
Cyclopropanes/chemistry , Imines/chemical synthesis , Oxindoles/chemical synthesis , Pyrrolidines/chemistry , Spiro Compounds/chemistry , Cycloaddition Reaction , Imines/chemistry , Molecular Structure , Oxindoles/chemistry , StereoisomerismABSTRACT
A new synthetic approach to biologically relevant spiro[pyrrolidine-3,3'-oxindoles] was developed on the basis of the cascade transformation of 3-(2-azidoethyl)oxindoles via Staudinger/aza-Wittig/Mannich reactions. The parent azides were readily synthesized through a nucleophilic ring opening of spiro[cyclopropane-1,3'-oxindoles] with the azide ion. A series of new spiro[pyrrolidine-3,3'-oxindoles] with various (het)aryl substituents at the C2 and C5 positions of the pyrrolidine ring were synthesized. In vitro experiments revealed their high cytotoxicity toward LNCaP and PC-3 tumor cell lines.
