Synthesis and evaluation of new steroidal lactam conjugates with aniline mustards as potential antileukemic therapeutics

Alkylating agents are still nowadays one of the most important classes of cytotoxic drugs, which display a wide range of therapeutic use for the treatment of various cancers. We have synthesized and tested four hybrid homo-azasteroidal alkylating esters for antileukemic activity against five sensitive to alkylating agents human leukemia cell lines in vitro and against P388 murine leukemia in vivo. Comparatively, melphalan and 3-(4-(bis(2-chloroethyl)amino)phenoxy)propanoic acid (POPAM) were also examined. All the homo-aza-steroidal alkylators showed relatively lower acute toxicity, very promising and antileukemic activity both in vitro and in vivo. © 2016 Elsevier Inc

8-Hydroxy-2’-Deoxyguanosine and 8-Nitroguanine Production and Detection in Blood Serum of Breast Cancer Patients in Response to Postoperative Complementary External Ionizing Irradiation of Normal Tissues

It is widely known that ionizing irradiation is strongly linked to the production of reactive oxygen (ROS) and nitrative species (RNS) through which DNA damage products like 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-nitroguanine (8-NG) are generated, respectively. In the present study, we aimed to investigate the formation of 8-OHdG and 8-NG upon irradiation and to further explore whether alterations in their concentration levels are related to the administered radiation doses and exposure time. Our research work was conducted in blood serum samples collected from 33 breast cancer patients who received adjuvant radiotherapy. The detection of 8-OHdG and 8-NG was assessed by enzyme-linked immunosorbent assay. Our results suggest that both, 8-OHdG and 8-NG, were formed during the radiation regimen. Significant correlations with radiation dose were also demonstrated by the dose-response curves of 8-OHdG and 8-NG, fitted by logarithmic distribution and polynomial regression, respectively. More precisely, 8-OHdG and 8-NG concentrations (ng/mL) were considerably increased when patients received ionizing radiation up to 30 Gy whereas irradiation over 30 Gy did not induce any further increases. The current study supports a) the production of 8-OHdG and 8-NG during radiotherapy and b) significant correlations between either 8-OHdG or 8-NG levels and radiation doses, indicating a radiation-dose-dependent relationship. © The Author(s) 2020

Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: From bench to bedside?

Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in-vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Synthesis and anticancer activity of novel 3,6-disubstituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives

The development of new antitumor agents is one of the most pressing research areas in medicinal chemistry and medicine. The importance of triazole and thiadiazole rings as scaffolds present in a wide range of therapeutic agents has been well reported and has driven the synthesis of a large number of novel antitumor agents. The presence of these heterocycles furnishes extensive synthetic possibilities due to the presence of several reaction sites. Prompted by these data we designed, synthesized and evaluated a series of novel 3,6-disubstituted 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives as potential anticancer agents. We emphasized in the strategy of combining two chemically different but pharmacologically compatible molecules (the 1,2,4-triazole and 1,3,4 thiadiazole) in one frame. Several of the newly synthesized 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives showed substantial cytostatic and cytotoxic antineoplastic activity invitro, while they have produced relatively low acute toxicities invivo, giving potentially high therapeutic ratios. Insilico screening has revealed several protein targets including apoptotic protease-activating factor 1 (APAF1) and tyrosine-protein kinase HCK which may be involved in the biological activities of active analogues. © 2016 The Author

In silico study of potential antiviral activity of copper(II) complexes with non–steroidal anti–inflammatory drugs on various SARS–CoV–2 target proteins

In silico molecular docking studies, in vitro toxicity and in silico predictions on the biological activity profile, pharmacokinetic properties, drug–likeness, ADMET (absorption, distribution, metabolism, excretion, and toxicity) physicochemical pharmacokinetic data, and target proteins and toxicity predictions were performed on six copper(II) complexes with the non–steroidal anti–inflammatory drugs ibuprofen, loxoprofen, fenoprofen and clonixin as ligands, in order to investigate the ability of these complexes to interact with the key therapeutic target proteins of SARS–CoV–2 (Severe Acute Respiratory Syndrome Coronavirus 2) 3C–like cysteine main protease (3CLpro/Mpro), viral papain–like protease (PLpro), RNA–dependent RNA polymerase (RdRp), and non–structural proteins (Nsps) Nsp16–Nsp10 2′–O–methyltransferase complex, and their capacity to act as antiviral agents, contributing thus to understanding the role they can play in the context of coronavirus 2019 (COVID–19) pandemic. Cytotoxic activity against five human cancer and normal cell lines were also evaluated. © 2022 Elsevier Inc

Novel c(RGDyK)-based conjugates of POPAM and 5-fluorouracil for integrin-targeted cancer therapy

Aim: Alkylating agents and antimetabolites are cytotoxic drugs commonly used in cancer treatment. These medications are often associated with serious side effects on normal tissues and organs. Methodology: To improve the pharmacological profile of the alkylating agent POPAM and the antimetabolite 5-fluorouracil, novel integrin-targeted delivery systems based on c(RGDyK) were successfully synthesized. The new conjugates were tested in vitro against different cancer cells such as PC3, SKOV3, A549, MCF7 and MBA-MB-321. Results & conclusion: The c(RGDyK) conjugates of POPAM demonstrated better inhibitory effects and selectivity compared with c(RGDyK) and POPAM. The c(RGDyK) conjugates of 5-FUA demonstrated diverse inhibitory effects compared with c(RGDyK) and 5-FUA related to the levels of integrin expression, the conjugate stability and sensitivity of cancer cells to 5-FUA. © 2017 2017 Future Science Ltd

Synthesis and biological studies of c(RGDyK) conjugates of cucurbitacins

Cucurbitacins (CUCUs) are triterpenoids known to display potent cytotoxic effects; however, their clinical application is limited due to poor pharmacokinetics and systemic toxicity. This work focuses on the development of c(RGDyK)-CUCU conjugates for the selective delivery of CUCUs to integrin-overexpressing cancer cells. The activity of the conjugates against various cancer cells was studied. They exhibited a mild cytostatic effect to six cancer cell lines and a cytotoxic effect against integrin-overexpressing MCF-7 and A549 cells. Their chemical and metabolic stability was extensively studied using LC-MS analysis. The conjugates maintained high affinity for αvβ3 integrin receptors. c(RGDyK) conjugation via a PEG linker was beneficial for CUCU-D and the resulting conjugate was approximately three-times more active than the free CUCU-D in MCF7 cells. © 2021 S. Karger AG, Basel

Synthesis and analysis of the anticancer activity of Ru(II) complexes incorporating 2-hydroxymethylidene-indene-1,3-dione ligands

2-Hydroxymethylidene-indene-1,3-diones bearing alkoxyvinyl, pyrrolyl, and indolyl groups were synthesized by thermal decomposition of the phenyliodonium ylide of lawsone and served as ligands for the preparation of piano-stool Ru(ii) complexes. The reactivity of the new compounds with biomolecules and their stability in aqueous solution have been studied. The synthesized complexes have been tested for their anticancer activity against four human ovarian cancer cell lines (OVCAR-5, SKOV-3, UWB1.289, and UWB1.289 + BRCA1) in order to investigate their structure-activity relationships. The ruthenium complexes bearing the dihydrofuryl, the 2-(butoxy)vinyl, and the 2-(isobutoxy)vinyl substituents were the most potent compounds identified in this screen with IC50 values in the range of 22-82 μM. Complexes 11d, 11a, and 11b were found to be more active than cisplatin against the SKOV3 human ovarian cancer cells. © 2017 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique

Synthesis and Biological Evaluation of a c(RGDyK) Peptide Conjugate of SRPIN803

In the present study, SRPIN803 and c(RGDyK)-SRPIN803 hybrid compounds were efficiently synthesized and evaluated for their stability in human plasma and buffers of pH 7.4 and 5.2. The hybrids were mainly cytostatic against a panel of tested cancer cells, whereas one c(RGDyK)-SRPIN803 hybrid, geo35, was the most active compound in this screen and was cytotoxic against cell lines MCF7 and MRC5 with IC50 values of 61 and 63 μM, respectively. SRPIN803 and geo35 exhibited antiangiogenic activity in zebrafish embryos, and this effect was dose-dependent. Although c(RGDyK)-SRPIN803 hybrid compounds were found less potent compared to SRPIN803, they have shown activities interesting enough to illustrate the potential of this approach for the development of a new class of antiangiogenic compounds. © 2021 The Authors. Published by American Chemical Society

Silver complexes with heterocyclic thioamide and tertiary arylphosphane ligands: Synthesis, crystal structures, in vitro and in silico antibacterial and cytotoxic activity, and interaction with DNA

Herein we report on the synthesis and molecular structures of six silver(I) mixed-ligand complexes containing a heterocyclic thioamide [4-phenyl-imidazole-2-thione (phimtH) or 2,2,5,5-tetramethyl-imidazolidine-4-thione (tmimdtH)] and a tertiary arylphosphane [triphenylphosphine (PPh3), tri-o-tolylphosphane (totp)] or diphosphane [(1,2-bis(diphenylphosphano)ethane (dppe), bis(2-diphenylphosphano-phenyl)ether (DPEphos) or 4,5-bis(diphenylphosphano)-9,9-dimethylxanthene) (xantphos)]. The interaction of the compounds with calf-thymus DNA (CT DNA), as monitored directly via UV–vis spectroscopy and DNA-viscosity measurements and indirectly via its competition with ethidium bromide for DNA-intercalation sites, is suggested to take place via an intercalative mode. The new complexes show selective significant in vitro antibacterial activity against four bacterial strains. The antiproliferative effects and cytostatic efficacies of the complexes against four human cancer cell lines were evaluated. The best cytostatic and cytotoxic activity was appeared for the complexes bearing the phimtH moiety. In order to explain the described in vitro activity of the complexes, and to approach a possible mechanism of action, molecular docking studies were adopted on the crystal structure of CT DNA, DNA-gyrase, human estrogen receptor alpha and a cell-cycle specific target protein, human cyclin-dependent kinase 6. © 2020 Elsevier Inc