17 research outputs found
Spectroscopic Studies of Fluorescence Effects in Bioactive 4-(5-Heptyl-1,3,4-Thiadiazol-2-yl)Benzene-1,3-Diol and 4-(5-Methyl-1,3,4-Thiadiazol-2-yl)Benzene-1,3-Diol Molecules Induced by pH Changes in Aqueous Solutions
The influence of effective microorganisms (EM) and yeast on the degradation of strobilurins and carboxamides in leafy vegetables monitored by LC-MS/MS and health risk assessment
The effect of different homo-aza-steroidal esters of m-N,N-bis(2-chloroethyl) aminocinamic acid on mutation induction in the Salmonella typhimurium/mammalian microsome test
The effect of different homo-aza-steroidal esters of m-N,N-bis-(2-chloroethyl)amino cinnamic acid on SCEs, chromosomal aberration frequencies and protein synthesis rate in human lymphocyte cultures
Lactandrate: A D-homo-aza-androsterone alkylator in the treatment of breast cancer
The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3β-hydroxy-13α-amino-13,17-seco- 5α-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERα) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers. © Springer 2005
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
The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-α
In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-α (ERα) was investigated. ESBL was found to be positioned inside the binding cavity with its steroidal moiety, whereas the alkylating moiety protruded out of receptor's pocket. Copyright © 2006 Cognizant Comm. Corp
Preclinical studies on NSC290205 aza-steroid alkylator activity in combination with adriamycin against lymphoid leukaemia
NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a
combination of a D-lactam derivative of androsterone and an alkylating
derivative of N,N-bis(2-chloroethyl)aniline. We tested NSC290205 for
synergistic antileukaemic activity with adriamycin (ADR), (i) in vitro
against the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and
RPMI-8226, (ii) in vivo against P388 lymphocytic and L1210 lymphoid
murine leukaemias (at incipient and advanced phase). Our results
indicated significant cytostatic and cytotoxic synergy of NSC290205 and
ADR in vitro. We further examined these results in vivo by replacing
cyclophosphamide in the standard CHOP (cyclophosphamide,
hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP)
and comparing the efficiency of these two regimens in vivo. Although
treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone
yielded equivalent results, AHOP produced a clear benefit for survival
compared with CHOP against advanced leukaemias, confirming the in vitro
observations [higher percentage increase in median lifespan of treated
animals over the untreated (control): 188% and 239% in L1210, 308%
and 353% in P388, P < 0.01, for CHOP and AHOP respectively]. AHOP also
proved to be more genotoxic and cytostatic than CHOP, inducing higher
sister chromatid exchange levels and cell division delays on P388 cells
in vivo. NSC290205 showed superior antineoplastic potential against
lymphoid leukaemia and significant synergy with ADR, producing an
excellent therapeutic outcome