New Esters of Ferrediol and Sideritriol in subsp. : Characterization and Antiproliferative Activity.

17-Isovalerate esters of ferrediol and sideritriol (compounds and ) and 17-(2-methylbutyrate) ferrediol (compound ), which have not been earlier described, were isolated along with five known -15-kaurene diterpenes (siderol, sideridiol, sideroxol, eubotriol, and -candicandiol), one -beyerene (flavovirol), and one phytosterol (β-sitosterol) from the aerial parts of subsp. (Boiss. & Heldr.

Identification of new multi-substituted 1H-pyrazolo[3,4-c]pyridin-7(6H)-ones as soluble guanylyl cyclase (sGC) stimulators with vasoprotective and anti-inflammatory activities.

Herein, we describe the rational design, synthesis and in vitro functional characterization of new heme-dependent, direct soluble guanylyl cyclase (sGC) agonists. These new compounds bear a 1H-pyrazolo[3,4-c]pyridin-7(6H)-one skeleton, modified to enable efficient sGC binding and stimulation. To gain insights into structure-activity relationships, the N6-alkylation of the skeleton was explored, while a pyrimidine ring, substituted with various C5'-polar groups, was installed at position C3.

An Optimized Cloud Computing Method for Extracting Molecular Descriptors.

Extracting molecular descriptors from chemical compounds is an essential preprocessing phase for developing accurate classification models. Supervised machine learning algorithms offer the capability to detect "hidden" patterns that may exist in a large dataset of compounds, which are represented by their molecular descriptors. Assuming that molecules with similar structure tend to share similar physicochemical properties, large chemical libraries can be screened by applying similarity sourcing techniques in order to detect potential bioactive compounds against a molecular target.

Design, synthesis and biological evaluation of new 3,4-dihydroquinoxalin-2(1)-one derivatives as soluble guanylyl cyclase (sGC) activators.

Herein, we present the structure-based design, synthesis and biological evaluation of novel mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1)-one derivatives as potential heme-independent activators of soluble guanylate cyclase (sGC). Docking calculations of several known sGC agonists by utilizing both a homology model of human sGC Η-ΝΟΧ domain and a recent cryo-EM structure of the same domain guided the structural optimization of various designed compounds. Among these, mono- and di-carboxylic 3,4-dihydroquinoxalin-2(1)-one derivatives arose as promising candidate sGC activators.

Targeting androgen receptor for prostate cancer therapy: From small molecules to PROTACs.

Prostate cancer (PCa) remains a serious type of cancer for men worldwide. The majority of new PCa cases are associated with androgen receptor (AR) hyperactivity. Various AR-targeting molecules that suppress its activity have been discovered.

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration.

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and αβ integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration.

Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells.

A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20-28 showed IC values in the range of 0.019µM-0.

Potentiation by caffeine of cytogenetic damage induced by steroidal derivatives in human lymphocytes in vitro.

We studied the effects of three newly synthesized steroidal derivatives of nitrogen mustards, alone or in combination with caffeine, on sister chromatid exchange (SCE) frequencies and on human lymphocyte proliferation kinetics. The agents have as alkylator functionalities either P-N,N-bis(2-chloroethyl)aminophenyl-buturate (CHL) or P-N,N-bis(2-chloroethyl)aminophenyl-acetate (PHE), esterified with a modified steroidal nucleus. An enhancement of SCE frequency was seen with compounds which contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17-position of the D-ring.

Steroidal esters of the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl)amino-phenyl]butanoic acid (2-PHE-BU): synthesis and in-vivo biological evaluation.

On the basis of the results of in-silico predictions and in an effort to extend our structure-activity relationship studies, the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl) amino-phenyl]butanoic acid (2-PHE-BU) was synthesized and conjugated with various steroidal alcohols. The resulting steroidal esters were evaluated for their in-vivo toxicity and antileukemic activity in P388-leukemia-bearing mice. The new derivatives showed significantly reduced toxicity and marginally improved antileukemic activity compared with free 2-PHE-BU.

Cytogenetic and antineoplastic effects by newly synthesised steroidal alkylators in lymphocytic leukaemia P388 cells in vivo.

New compounds with potential antitumour activity were synthesised by combining nitrogen mustard with the steroidal skeleton, in an effort to improve specificity and at the same time reduce systemic toxicity. The steroidal part is aimed to serve as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties. The purpose of the present investigation was to evaluate these compounds for anti-neoplastic activity.

Synergistic cytogenetic and antineoplastic effects by the combined action of esteric steroidal derivatives of nitrogen mustards.

We studied the effect of five newly synthesized steroidal derivatives of nitrogen mustards. These derivatives have as alkylators either P-N, N-bis(2-chloroethyl)aminophenyl-butyrate (CHL) or P-N, N-bis(2-chloroethyl)aminophenyl-acetate (PHE) groups esterified with different modified steroidal nuclei. We examined them alone or in combination, on sister chromatid exchange rates and on human lymphocyte proliferation kinetics.

Pyrrolo[2,3-α]carbazole derivatives as topoisomerase I inhibitors that affect viability of glioma and endothelial cells in vitro and angiogenesis in vivo.

Topoisomerase I is one of the most significant molecular targets through which indolocarbazoles inhibit tumour growth. In the present work, we studied the effect of new pyrrolo[2,3-α]carbazole derivatives on topoisomerase I activity in vitro, as well as on the viability of glioma and endothelial cells in vitro and on angiogenesis in vivo. All the tested compounds significantly decreased topoisomerase I activity in a concentration dependent manner, with the most effective being 1c, 1d(1), 1d(2) and 1f.

20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR.

A novel approach to indoloditerpenes by Nazarov photocyclization: synthesis and biological investigations of terpendole E analogues.

The application of the Nazarov photocyclization as a mild and efficient method for access to the basic core of novel indoloditerpenoid derivatives is reported. The detailed synthesis of these new analogues of terpendole E, as well as their evaluation as potential inhibitors of KSP, is described.

Cytogenetic and antineoplastic effects of modified steroidal alkylators.

Introduction: The aim of this study was to design new potentially antineoplastic agents by combining nitrogen mustard with steroidal skeleton, in an effort to improve specificity and simultaneously to reduce systemic toxicity. The steroidal part is aimed to act as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties.

Materials And Methods: The compounds tested have, as alkylating agents, either p-N,N-bis(2-chloroethyl)aminophenyl-butyrate or p-N,N-bis(2-chloroethyl)aminophenyl-acetate esterified with a modified steroidal nucleus.

Tricyclic indole and dihydroindole derivatives as new inhibitors of soluble guanylate cyclase.

The synthesis of new tricyclic fused indole and dihydroindole derivatives and preliminary results from their in vitro inhibitory activity against soluble guanylate cyclase (sGC) are presented.

Synthesis, in vivo antileukemic evaluation and comparative study of novel 5alpha-7-keto steroidal esters of chlorambucil and its active metabolite.

Recent structure-antileukemic activity studies showed that the steroidal part of complex molecules containing DNA alkylators does not play only the role of the "biological carrier". New such compounds designed to possess an allylic 7-ketone showed enhanced antileukemic potency compared with derivatives with a simple steroidal skeleton. In order to investigate whether the enhancement of the antileukemic potency is attributed to the introduction of the 7-ketone or to the Delta5-7-keto conjugated steroidal system we decided to reduce the Delta5 double bond.

Rational design, synthesis, and in vivo evaluation of the antileukemic activity of six new alkylating steroidal esters.

The synthesis and the in vivo evaluation against leukemias P388 and L1210 of six new alkylating steroidal esters are described. The esteric derivatives incorporating the 17beta-acetamido-B-lactamic steroidal skeleton exhibited increased antileukemic activity and lower toxicity, compared to the 17beta-acetamido-7-keto analogs. Among the 17beta-acetamido-B-lactamic steroidal esters, the most potent compound afforded four out of six cures in leukemia P388 and was measured to be almost non-toxic, producing significant low levels of toxicity.

Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations.

Pyrrolo[2,3- a]carbazole derivatives were synthesized, and their effects on CDK1/cyclinB activity were evaluated. The most potent and efficacious inhibitor was found to be ethyl 9-chloro-1H-pyrrolo[2,3-alpha]carbazole-2-carboxylate (1e), exhibiting an IC50 in the low micromolar range and leading to 90% at higher concentrations. Using a computational model for CDK1-1e, binding we have observed that 1e exhibited two likely binding modes in the ATP-binding cleft that involve interactions with Lys130, Thr14, and Asp146 of the enzyme.

Structure-antileukemic activity relationship study of B- and D-ring modified and nonmodified steroidal esters of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid: a comparative study.

This study was designed as a rational continuation of our research regarding the functional requirements essential for the antileukemic activity of compounds comprising an alkylating moiety and a modified steroid. The steroidal esteric derivatives of 4-methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid were tested on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Among them the B-lactamic steroidal esters proved more potent antileukemic agents than the 7-oxidized and those with a simple B-ring, but not more effective inducers of DNA damage and cell cycle arrest in vitro.

Antileukemic and cytogenetic activity by triple administration of three modified steroidal derivatives of nitrogen mustards.

Combination chemotherapy is widely and routinely used for most cancer patients. The main objective of this study is an effort to develop new anticancer drugs and procedures with enhanced antitumor activity and reduced toxicity. This study was designed to determine the antileukemic and cytogenetic activity of five mixtures of three specific steroidal esters of aromatic nitrogen mustards in different proportions.

Rational design, synthesis and in vitro evaluation of three new alkylating steroidal esters.

Recent studies have indicated that minor functional changes on the steroidal part of complex molecules, comprising of an alkylating moiety and a steroidal congener, lead to compounds with enhanced biological activity. The observed induction of the genotoxic, cytotoxic and antileukemic effects suggest a determinative role of the steroidal congener on the mechanism of action. In order to further elucidate the structural requirements responsible for this, we designed and synthesized a new modified steroid, carrying a 17beta-acetamide substituent and a B lactamic ring, and studied the ability of its esters with three potent nitrogen mustards to induce sister chromatid exchange (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro.

Structure-anti-leukemic activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil.

In order to study the role of the steroidal moiety on the expression of anti-leukemic activity, we synthesized six derivatives of chlorambucil (CHL), and tested them on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Five of the six tested compounds produced submultiple toxicity, while the measured anti-leukemic potency was significantly increased. The lactamization of the B-steroidal ring rendered the molecules more potent, but the corresponding 7-oxidized derivatives proved better in both leukemias tested.

Structure-anti-leukemic activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil's active metabolite.

We have studied the effect of modification of the B-steroidal ring to lactamic on the anti-leukemic potency of D-modified and D-non-modified steroidal esters of chlorambucil's active metabolite. The compounds synthesized were studied against leukemias P388 and L1210 after the subsequent estimation of their toxicity in vivo, and for their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro. The in vitro results correlated well, on a molar basis, with the results obtained from the study of the anti-leukemic potency.

2D NMR and conformational analysis of a prototype anti-tumour steroidal ester.

The synthetic 3beta-hydroxy-17alpha-aza-d-homo-5-androsten-7,17-dione-p-N-N-bis(2-chloroethyl)aminophenylacetate (SOT-19, I) was found to be a very potent anti-leukaemic agent candidate. Its high biological activity and low toxicity rationalize the study of its conformational properties. It can also serve as a prototype and therefore as a template for a series of congener compounds possessing a variety of toxicity and anti-leukaemic activity in subsequent 3D-QSAR studies.