ABSTRACT
As a part of our investigations into the structural-activity relationship studies of a novel class of medicinally active 16-substituted steroids, several new 16-imidazolyl substituted steroidal derivatives have been synthesized and pharmacologically evaluated in the current study. The new steroidal analogues 5, 6, 8, 9, 11 and 12 exhibited moderate cytotoxic effects in sixty cancer cell lines derived from nine cancers types. The imidazolyl substituted steroidal derivatives 6 (DPJ-RG-1241) and 7 (RB-401) were obtained as the powerful inhibitors of aromatase with IC50=0.18 µM and IC50=0.168 µM, respectively, approximately 1.2 and 1.4 times more potent in comparison to standard drug exemestane. The bis-quaternary steroids 13 and 14 displayed potent skeletal muscle relaxant properties. An affinity constant of 0.007 µM was observed for compound 14 on frog rectus abdominis muscle preparation and 13 displayed a very high anticholinesterase activity K(i)=25 nM, approximately 115-fold higher in comparison to standard drug galanthamine (K(i)=2.9 µM).
Subject(s)
Chemistry Techniques, Synthetic/methods , Drug Design , Imidazoles/chemistry , Steroids/chemical synthesis , Steroids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Steroids/chemistryABSTRACT
Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and evaluated for their cytotoxic and aromatase inhibitory activity. The new steroidal analogues 3, 5-8 and 11 exhibited significant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung) and SF-268 central nervous system (CNS) at 100 µM and sensible cytotoxic effects subsequently in sixty cancer cell lines derived from nine cancers types (leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers). The imidazolyl substituted steroidal derivatives 5 and 7 exhibited strong inhibition of the aromatase enzyme with 16-[4-{3-(imidazol-1-yl)propoxy}-3-methoxybenzylidene]-5-androstene-3ß,17ß-diol (7) displaying 13 times more potency in comparison to aminoglutethimide.
Subject(s)
Androstenediols/chemical synthesis , Androstenedione/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Aromatase Inhibitors/chemical synthesis , Aromatase/chemistry , Steroids/chemistry , Androstenediols/chemistry , Androstenediols/toxicity , Androstenedione/chemical synthesis , Androstenedione/chemistry , Androstenedione/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Aromatase/metabolism , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/toxicity , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Steroids/chemical synthesis , Steroids/toxicityABSTRACT
Synthesis of eighteen new quaternary ammonium salts of 16E-arylidene androstene derivatives as skeletal muscle relaxants is reported in the present study. The effects of possibly extended interonium distances on muscle relaxant activity are discussed. All the quaternary ammonium steroids produced reduction in the twitch responses, when screened for in vitro neuromuscular blocking activity using isolated chick biventer cervicis muscle preparation. However, the variable interonium distance, which is believed to range from 11 to 17 Å in these quaternary compounds and is associated with the built in flexibility of these structures about the single bonds on the moieties linked to ring D of the steroid skeleton, resulted in varied degrees of muscle relaxant activity. Some of the compounds also inhibited acetylcholinesterase activity in low concentrations so that they would not be directly suitable for use as muscle relaxants.
Subject(s)
Androstenes/chemical synthesis , Neuromuscular Agents/chemical synthesis , Quaternary Ammonium Compounds/chemical synthesis , Acetylcholinesterase/metabolism , Androstenes/chemistry , Androstenes/pharmacology , Animals , Chickens , Neuromuscular Agents/chemistry , Neuromuscular Agents/pharmacology , Neuromuscular Blocking Agents/chemical synthesis , Neuromuscular Blocking Agents/chemistry , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacologyABSTRACT
Varied positioning of the hydroximino group on the parental steroid skeleton results in remarkable changes in the antineoplastic activity profile of the compounds. Here, the compound 7-oximino-5-androstene and its O-alkylated derivatives have been prepared and screened for cytotoxic and aromatase inhibitory activity. The steroidal 7-oximino ether derivatives exhibited insignificant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung), and SF-268 (CNS) at 100 microM. However, the imidazolyl-substituted steroidal oxime ethers displayed moderate inhibition of cytochrome P450 aromatase.
Subject(s)
Androstenes/chemical synthesis , Androstenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Aromatase Inhibitors/pharmacology , Alkylation , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Humans , Structure-Activity RelationshipABSTRACT
The synthesis and cytotoxic studies of a new series of 16E-arylidene androstene derivatives are reported herein. The impact of incorporating bis-tertiary amino functionalities in the steroid skeleton on cytotoxicity has also been observed. The compounds have been evaluated at National cancer Institute, Bethesda, Maryland, USA for their antineoplastic activity against various tumor cell lines. The synthesized 16E-arylidenosteroids exhibited significant cytotoxicity. Bis-tertiary amino steroid 29 possessing a diethylaminoalkoxy functionality was the most promising compound of the series with a total IP and SC score of 20 in in vivo hollow fiber assay and was selected for further detailed in vivo xenograft testing.
Subject(s)
Androstenes/chemical synthesis , Androstenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Androstenes/chemistry , Animals , Antineoplastic Agents/chemistry , Biological Assay , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Mice , National Cancer Institute (U.S.) , Quantitative Structure-Activity Relationship , Transplantation, Heterologous , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/pathology , United StatesABSTRACT
A new series of N-substituted imide derivatives have been synthesized by treating phthalic anhydride, naphthalic anhydride and their substituted derivatives with 2-hydrazino-1-imidazoline hydrobromide, various para-substituted aryl amines, aminoglutethimide and 2,4-dinitrophenyl hydrazine. Compounds 9, 10, 12, 18, 19, 23, 24 and 34-36 have been selected and screened for antineoplastic activity by National Cancer Institute, Bethesda, USA. Some newer aminoglutethimide derivatives 37-39 have also been prepared in order to study the effect of N-substitution on its pharmacological profile for the treatment of carcinoma. These compounds (37-39) have exhibited weak inhibition of human placental aromatase as compared to aminoglutethimide.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aromatase Inhibitors/chemical synthesis , Imides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Imides/chemistry , Imides/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
In the steroidal nucleus of 16-[4-(3-chloropropoxy)-3-methoxybenzylidene]-17-oxoandrost-5-en-3 beta-ol, C(30)H(29)ClO(4), (I), the outer two six-membered rings are in chair conformations, while the five-membered ring and the central six-membered ring of the steroidal nucleus adopt half-chair and envelope conformations, respectively. In 16-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)benzylidene]-3 beta-pyrrolidinoandrost-5-en-17 beta-ol monohydrate, C(37)H(54)N(2)O(3).H(2)O, (II), one C atom of one of the outer six-membered rings of the steroid nucleus and the four C atoms of the ethoxypyrrolidine ring are disordered over two sites. The five-membered ring, and the central and one of the outer six-membered rings of the steroidal nucleus exhibit distorted half-chair, chair and envelope conformations, respectively. In (I), intermolecular O-H...O hydrogen bonds link the molecules into chains via a co-operative O-H...O-H...O-H pattern. In (II), intermolecular O-H...O and O-H...N hydrogen bonds link the steroid and water molecules alternately into extended chains.
Subject(s)
Androstenes/chemistry , Hydrogen-Ion Concentration , Pyrroles/chemistry , Models, MolecularABSTRACT
Various steroidal oxime ether derivatives in androstene and estrane series have been synthesized and evaluated for the antineoplastic activity at National Cancer Institute, Bethesda, Maryland, USA. O-alkylation of the oximes by various alkylaminoethyl halides gave the oxime ether derivatives. The 17alpha-ethynylandrostene derivatives 29 (DPJ-684), 30 (DPJ-685), 31 (DPJ-686) and estrane derivatives 35 (DPJ-531) and 36 (DPJ-532) were among the small percentage of compounds, which have been screened by NCI for in vivo hollow fiber assay by virtue of their activity against one or more human tumour cell lines in 60 cell line in vitro prescreen. The preliminary in vivo reports of hollow fiber assays have been referred to the Biological Evaluation Committee for Cancer Drugs for considering these compounds for further detailed in vivo testing.
Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/pharmacology , Oximes/chemical synthesis , Oximes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , HumansABSTRACT
The title compound, C(36)H(49)NO(5).H(2)O, has the outer two six-membered rings of the steroid nucleus in chair conformations. The central ring B of the steroid nucleus is in an 8beta,9alpha-half-chair conformation, while ring D of the steroid adopts a slightly distorted 13beta,14alpha-half-chair conformation. The piperidine ring is in a chair conformation. The methoxybenzylidene moiety has an E configuration with respect to the carbonyl group at position 17. Intermolecular O-H.O and O-H.N hydrogen bonds link the steroid and water molecules into chains which run parallel to the b axis.
