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1.
Anticancer Drugs ; 24(1): 52-65, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23187313

ABSTRACT

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. Nevertheless, they did not prove to be superior either to the template steroidal ester used for in-silico predictions or to previously synthesized steroidal esters of aromatic nitrogen mustards. The results obtained indicate that in-silico design predictions may guide the design and synthesis of new bioactive steroidal esters, but further parameters should be considered aiming at the discovery of compounds with optimum activity.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Computer Simulation , Leukemia P388/drug therapy , Nitrogen Mustard Compounds/pharmacology , Animals , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Computer-Aided Design , Esters/chemistry , Female , Leukemia P388/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Nitrogen Mustard Compounds/chemical synthesis , Nitrogen Mustard Compounds/chemistry , Steroids/chemistry , Structure-Activity Relationship , Toxicity Tests
2.
In Vivo ; 22(3): 345-52, 2008.
Article in English | MEDLINE | ID: mdl-18610747

ABSTRACT

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. The 5alpha-7-keto-steroidal skeletons synthesized were tethered to chlorambucil and phenyl acetic acid's nitrogen mustard and studied against leukemia P338 in vivo. The reduction of the double bond had a negative impact on the antileukemic potency since the comparative study of the novel derivatives showed that a series of very potent Delta 5-7-keto-steroidal esters were converted by this modification to compounds with marginally accepted activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Chlorambucil/chemistry , Esters/chemical synthesis , Esters/therapeutic use , Leukemia/drug therapy , Steroids/chemistry , Animals , Antineoplastic Agents/chemistry , Catalysis , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Chlorambucil/metabolism , Esters/chemistry , Female , Hydrolysis , Male , Mice , Molecular Structure , Neoplasm Transplantation , Structure-Activity Relationship
3.
Bioorg Med Chem ; 16(9): 5207-15, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18353651

ABSTRACT

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.


Subject(s)
Antineoplastic Agents , Esters , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Steroids , Alkylation , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Esters/administration & dosage , Esters/chemical synthesis , Esters/chemistry , Female , Injections, Intraperitoneal , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Molecular Structure , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Stereoisomerism , Steroids/administration & dosage , Steroids/chemical synthesis , Steroids/chemistry , Structure-Activity Relationship
4.
Anticancer Drugs ; 18(9): 997-1004, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17704649

ABSTRACT

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. We speculate that these results indicate a different mechanism of action induced by the lactamized B steroidal ring, in comparison to the 7-keto or the D-lactamic groups, which involves the interaction of the -NHCO- moiety with cellularcomponents essential for tumor growth. 4-Methyl-3-N,N-bis(2-chloroethyl)amino benzoic acid proved a more proper module for the B-lactams than chlorambucil and phenyl acetic acid's nitrogen mustard probably because the esteric bond is less cleaved by the esterases, resulting in an increased concentration of the drug in the vinicity of the target site essential for an antineoplasmatic response.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Steroids/pharmacology , para-Aminobenzoates , 4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacology , 4-Aminobenzoic Acid/therapeutic use , 4-Aminobenzoic Acid/toxicity , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Esters , Female , Lethal Dose 50 , Male , Mice , Mice, Inbred Strains , Molecular Structure , Sister Chromatid Exchange , Steroids/chemistry , Steroids/therapeutic use , Steroids/toxicity , Structure-Activity Relationship
5.
Anticancer Drugs ; 17(5): 511-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16702807

ABSTRACT

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. The lactamization of the D-steroidal ring afforded potent compounds, regardless of the configuration of the B-ring. The best among all derivatives contains both chemical modifications and is intended as a promising key molecule that must be further studied. We speculate that in leukemic cells a tumor-specific protein is overexpressed, the steroid has the ability to bind and block this protein from carrying out its normal function, and the drug-protein complex prevents the repair of the adducts. The synthesis, physicochemical and spectroscopic data of these compounds and a modified route for the synthesis of CHL are also reported.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Chlorambucil/analogs & derivatives , Leukemia/drug therapy , Animals , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Cell Line, Tumor , Chlorambucil/chemistry , Chlorambucil/pharmacology , Female , Humans , Male , Mice , Neoplasms, Experimental/drug therapy , Structure-Activity Relationship
6.
Anticancer Drugs ; 16(10): 1075-82, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16222149

ABSTRACT

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. In a comparative study, the B-lactamic steroidal derivatives proved less active than the 7-oxidized ones against both leukemias. The presence of the -NHCO- group in the B-steroidal ring did not have the same positive effect on the biological action of chlorambucil's active metabolite esters as in the D-lactamic ring. However, this new modification of the B-ring rendered the final esteric derivatives much more toxic, compared with to the corresponding esters with a simple B-ring. This loss of the anti-leukemic specificity, which occurs from the modification of the B-ring, is additional evidence for the role of the steroidal part on the mechanism of action of these promising compounds. This provides support for the notion that the steroidal part of these molecules is not just a simple biological carrier, as has been speculated for many years.


Subject(s)
Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/therapeutic use , Chlorambucil/analogs & derivatives , Leukemia/drug therapy , Steroids/therapeutic use , Animals , Antineoplastic Agents, Alkylating/pharmacology , Cell Proliferation/drug effects , Chlorambucil/chemistry , Esters/chemistry , Esters/pharmacology , Esters/therapeutic use , Female , Lymphocytes/drug effects , Male , Mice , Mice, Inbred Strains , Molecular Structure , Sister Chromatid Exchange , Steroids/chemistry , Steroids/pharmacology , Structure-Activity Relationship
7.
Anticancer Drugs ; 15(10): 983-90, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15514568

ABSTRACT

We have investigated the role of the allylic 7-ketone in oxidized Delta5-steroids on antileukemic activity. We synthesized and studied a series of oxidized and non-oxidized steroidal esters of p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), chlorambucil's active metabolite. In a comparative study of these 7-keto derivatives, on a molecular basis, regarding their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro, the results with these 7-keto derivatives, on a molecular basis, correlated well with their antileukemic potency against leukemia P388- and L1210-bearing mice, which proved to be significantly increased compared to that of the non-oxidized derivatives. Our results indicate that the role of the steroidal skeleton it is not only for the transportation of the alkylating agent into the cell, but also contributes directly to the mechanism of antileukemic action, by an as-yet unknown way. The main conclusion from this study is that the existence of the allylic 7-keto group in the skeleton of the Delta5-steroidal esters impressively enhances their antileukemic activity, while the toxicity remains at clinically acceptable levels, suggesting that this structural modification should be further investigated.


Subject(s)
Androstenes/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Ketones/chemical synthesis , Phenylacetates/chemical synthesis , Androstenes/chemistry , Androstenes/pharmacology , Animals , Cell Proliferation/drug effects , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Female , Ketones/chemistry , Ketones/pharmacology , Lethal Dose 50 , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Lymphocytes/cytology , Lymphocytes/drug effects , Lymphocytes/ultrastructure , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Phenylacetates/chemistry , Phenylacetates/pharmacology , Sister Chromatid Exchange , Structure-Activity Relationship
8.
Steroids ; 68(7-8): 659-66, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12957671

ABSTRACT

A new synthetic procedure and a modification of the original method described in the literature for the synthesis of the steroidal B-D bilactam, 3 beta-hydroxy-7 alpha,17 alpha-diaza-B,D-dihomo-5-androsten-7,17-dione are reported. The key step in the modified method involved protection of the D-lactamic nitrogen atom of 3 beta-acetoxy-17 alpha-aza-D-homo-5-androsten-17-one using a reagent of specific electrophilicity (due to the stereoelectronic properties of the cyclic amide), as Beckmann rearrangement of the B-steroidal ring was hindered, possibly via long range effects, by the presence of the unprotected D-lactamic moiety. Using the 3 beta-acetoxy-5-androsten-17-one as starting material, a new synthetic procedure was developed through ketalization of the 17-ketone and allylic oxidation to the 7-ketone, which was subsequently followed by Beckmann rearrangement of the B- and D-steroid rings. Both approaches resulted in 45 and 67% yields of the desired B,D-bilactam, respectively, in contrast to the 15% yield, which has been reported in the literature.


Subject(s)
Androstenedione/analogs & derivatives , Androstenedione/chemical synthesis , Indicators and Reagents , Lactams/chemistry , Oximes/chemistry
9.
Steroids ; 68(5): 407-14, 2003 May.
Article in English | MEDLINE | ID: mdl-12798491

ABSTRACT

A variety of delta5-steroids were converted into alpha, beta-unsaturated 7-ketones using a modification of the already known method of t-butyl hydroperoxide in the presence of copper iodide in acetonitrile. The same alteration was applied to another oxidative procedure, which had never been used before on steroidal substrates. The same oxidative agent was used in the presence of copper iodide, and tetra-n-butylammonium bromide was used as a phase-transfer catalyst in a two-phase system of water/methylene chloride. It was found that the allylic oxidation proceeded more efficiently when t-butyl hydroperoxide was added to the reaction mixture in portions. The initial addition of the total amount of oxidant or its dropwise addition afforded low yields. This observation contributes to the investigation of the reaction mechanism, and high-yield conversions of steroidal 5,6-enes into the corresponding conjugated 7-ones in short reaction times are reported.


Subject(s)
Allyl Compounds/chemistry , Ketosteroids/chemical synthesis , Catalysis , Copper/chemistry , Iodides/chemistry , Molecular Structure , Oxidation-Reduction , Time Factors , tert-Butylhydroperoxide/chemistry
10.
Anticancer Res ; 22(4): 2293-9, 2002.
Article in English | MEDLINE | ID: mdl-12174917

ABSTRACT

The increase of the damaging effects on specific DNA sequences and the reduction of the subsequent toxicity of nitrogen mustards has been achieved by their chemical conjugation with modified steroids through an esteric bond. In an attempt to study the structure-activity relationships of these compounds, we synthesized eight steroidal esters of 4-methyl-3-bis(2-chloroethyl)aminobenzoic acid (4-Me-CABA). The anti-leukemic and cytogenetic effects of the parent alkylating agent were compared with those produced by the steroidal compounds, in vivo against leukemias P388 and L1210 and in vitro for induction of Sister Chromatid Exchanges (SCE) and on proliferation rate indices (PRI). The results demonstrate that the existence of the NH-CO group, either as an endocyclic lactamic or as an out of the ring amidic one but at axial conformation, at the steroid-carrier moiety is necessary for the expression of the antileukemic activity. The synthetic route for the preparation of the steroidal esters and their physicochemical data are also reported.


Subject(s)
4-Aminobenzoic Acid/pharmacology , Antineoplastic Agents/pharmacology , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Lymphocytes/cytology , Sister Chromatid Exchange/drug effects , 4-Aminobenzoic Acid/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Humans , Lymphocytes/drug effects , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Structure-Activity Relationship , para-Aminobenzoates
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