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1.
Chem Biol Interact ; 296: 179-184, 2018 Dec 25.
Article in English | MEDLINE | ID: mdl-30253125

ABSTRACT

The development of new targeted anticancer agents able to efficiently and specifically destroy cancer cells with minimal toxic side effects is nowadays a subject of intensive research endeavors. We report the conjugation of testo and testo-Pt(II) (two semi-synthetic testosterone derivatives) with calf thymus DNA in aqueous solution at physiological pH. Multiple spectroscopic methods, thermodynamic analysis and modeling were used to determine the binding efficacy of these drugs to DNA duplex. Thermodynamic parameters showed drug-DNA conjugation occurs via ionic interactions with testo-Pt(II) forming more stable DNA adducts than testo with Ktesto-DNA = 1.80 (±0.5) x 105 M-1 and Ktesto-Pt(II)-DNA = 2.3 (±0.8) x 105 M-1. Molecular modeling shows that testo and testo-Pt(II) bind DNA at different locations.


Subject(s)
Antineoplastic Agents/chemistry , DNA/chemistry , Organometallic Compounds/chemistry , Platinum/chemistry , Testosterone/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Cattle , Hydrogen-Ion Concentration , Models, Molecular , Organometallic Compounds/chemical synthesis , Thermodynamics
2.
PLoS One ; 7(1): e28395, 2012.
Article in English | MEDLINE | ID: mdl-22253690

ABSTRACT

In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous leukaemia (CML). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the mode of apoptin's action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions that were first predicted in silico. This structure-property relationship of apoptin may help in unlocking its cancer-selective toxic properties. Moreover, such models will guide us in developing of a new class of potent apoptin-like molecules with greater selectivity and potency.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Capsid Proteins/metabolism , Drug Design , Fusion Proteins, bcr-abl/metabolism , Models, Molecular , Nuclear Proteins/metabolism , Adaptor Proteins, Signal Transducing/chemistry , Amino Acid Motifs , Amino Acid Sequence , Amino Acids/metabolism , Animals , Capsid Proteins/chemistry , Capsid Proteins/toxicity , Cell Death/drug effects , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Computational Biology , Down-Regulation/drug effects , Fusion Proteins, bcr-abl/chemistry , Humans , Hydrogen Bonding/drug effects , Mice , Molecular Sequence Data , Nuclear Proteins/chemistry , Phosphorylation/drug effects , Protein Binding/drug effects , Protein Transport/drug effects , Sequence Alignment , Sequence Homology, Amino Acid , Signal Transduction/drug effects , Structural Homology, Protein , src Homology Domains
3.
Steroids ; 76(1-2): 94-103, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20869376

ABSTRACT

The synthesis of a series of 17ß-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2'-aminoethyl)pyridine ligand. They are prepared from estrone in only 5 chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231). The novel PEG-hybrids are also compared in terms of activities with two other families of 17ß-estradiol-platinum(II) hybrids that we reported in previous studies. Molecular modeling study performed on a representative member of each family of hybrids reveals distinct molecular interactions with the estrogen receptor α which further corroborates their notably contrasting cytocidal activities on breast cancer cell lines. This study also shows that lipophilicity and the orientation of the tether chain between the estrogenic portion and the platinum(II) core contribute markedly to the biological activity of the various families of hybrids. The most active hybrids are those possessing an alkyl tether chain at position 16ß of the steroid nucleus. For example, derivative 3 (p=6) is about 16 times more potent on MCF-7 breast cancer cells than the corresponding 16α-PEG-hybrids (2b) made in this study.


Subject(s)
Antineoplastic Agents/pharmacology , Estradiol/chemistry , Organometallic Compounds/pharmacology , Platinum/chemistry , Polyethylene Glycols/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Estrogen Receptor alpha/chemistry , Humans , Models, Molecular , Molecular Conformation , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Stereoisomerism
4.
Eur J Pharmacol ; 625(1-3): 90-100, 2009 Dec 25.
Article in English | MEDLINE | ID: mdl-19835861

ABSTRACT

In this article, current knowledge of drug design is reviewed and an approach of rational drug design is presented. The process of drug development is challenging, expensive, and time consuming, although this process has been accelerated due to the development of computational tools and methodologies. The current target based drug design approach is incomplete because most of the drugs developed by structure guided approaches have been shown to have serious toxic side effects. Otherwise these drugs would have been an ideal choice for the treatment of diseases. Hence, rational drug design would require a multidisciplinary approach. In this regard, incorporation of gene expression technology and bioinformatics tools would be indispensable in the structure based drug design. Global gene expression data and analysis of such data using bioinformatics tools will have numerous benefits such as efficiency, cost effectiveness, time saving, and will provide strategies for combination therapy in addition to overcoming toxic side effects. As a result of incorporation of gene expression data, partial benefit of the structure based drug design is slowly emerging and rapidly changing the approach of the drug development process. To achieve the full benefit of developing a successful drug, multidisciplinary approaches (approaches such as computational chemistry and gene expression analysis, as discussed in this article) would be necessary. In the future, there is adequate room for the development of more sophisticated methodologies.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Computational Biology/methods , Computer-Aided Design , Drug Delivery Systems , Gene Expression Profiling/methods , Humans , Neoplasms/genetics , Neoplasms/physiopathology
5.
Bioorg Med Chem Lett ; 18(14): 3982-7, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18571403

ABSTRACT

A series of benzopyran-based platinum complexes of types 4 and 5 were synthesized as potential anticancer agents. The novel compounds were synthesized in several steps using simple and efficient chemistry. The newly synthesized compounds were evaluated for their biological efficacy and showed significant in vitro cytotoxic activity in different hormone-dependent and -independent breast cancer cell lines. Docking and other molecular modeling experiments were also performed for one of the potent compounds, 5f, which showed that both the possible enantiomeric forms (5f with 3R,4R and 5f with 3S,4S) of the molecule have comparable lowest energy (for 5f with 3R,4R, -31.953 kcal/mol and for 5f with 3S,4S, -31.944 kcal/mol). The 3D QSAR was examined for the derivatives of both enantiomeric forms and a novel relationship for the 3S,4S derivatives is discussed.


Subject(s)
Benzopyrans/chemical synthesis , Breast Neoplasms/drug therapy , Organoplatinum Compounds/chemical synthesis , Antineoplastic Agents/pharmacology , Benzopyrans/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Structure , Organoplatinum Compounds/chemistry , Quantitative Structure-Activity Relationship , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 18(7): 2282-7, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18356047

ABSTRACT

The synthesis of a series of 17beta-estradiol-platinum(II) hybrid molecules is reported. The hybrids are made of a PEG linking chain of various length and a 2-(2'-aminoethyl)pyridine ligand. They are prepared from estrone in five chemical steps with an overall yield of 22%. The length of the PEG chain does not influence the solubility of the compounds as it remains relatively constant throughout the series. MTT assays showed that the derivative with the longest PEG chain showed the best activity against breast cancer cell lines (MCF-7 and MDA-MB-231). Molecular modeling study rationalized the results.


Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Cell Line, Tumor/drug effects , Estradiol/analogs & derivatives , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Estradiol/chemical synthesis , Estradiol/pharmacology , Female , Humans , Ligands , Models, Chemical , Organoplatinum Compounds/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 17(17): 4955-60, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17596942

ABSTRACT

Breast cancer, a leading cause of mortality in women, warrants the development and biological evaluation of new anticancer agents. A novel series of thiopyridine triazine derivatives was synthesized and investigated in the human breast cancer cell line, MDA-MB-468. SM40, the most potent derivative, induced a G2/M arrest and apoptosis with a possible involvement of p53. The cytotoxicity of SM40 was also examined against the NCI 60 cell line panel and its potency was rationalized using molecular modeling. Results suggest that SM40 is a promising cytotoxic agent.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Breast Neoplasms/drug therapy , Cell Division , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , G2 Phase , Humans , Hydrogen Bonding , Models, Chemical , Models, Molecular , Molecular Conformation , Pyridines/chemistry , Triazines/chemistry
8.
Bioorg Med Chem Lett ; 17(8): 2139-45, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17321743

ABSTRACT

A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , G1 Phase/drug effects , Platinum/pharmacology , Triazines/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cattle , Cell Line, Tumor , Computer Simulation , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Drug Screening Assays, Antitumor , Female , Humans , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Platinum/therapeutic use , Protein Binding , Structure-Activity Relationship , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , Triazines/pharmacology , Tumor Suppressor Protein p53/metabolism
9.
Cancer Res ; 65(13): 5696-702, 2005 Jul 01.
Article in English | MEDLINE | ID: mdl-15994944

ABSTRACT

S100A7 is among the most highly expressed genes in preinvasive breast cancer, is a marker of poor survival when expressed in invasive disease, and promotes breast tumor progression in experimental models. To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth. This effect is paralleled by increased activity of nuclear factor-kappaB (3-fold) and phospho-Akt (4-fold), which are known to mediate prosurvival pathways. S100A7 and phospho-Akt are also correlated in breast tumors examined by immunohistochemistry (n = 142; P < 0.0001; r = 0.34). To explore the underlying mechanism, we examined the role of a putative c-Jun activation domain-binding protein 1 (Jab1)-binding domain within S100A7 using a panel of MDA-MB-231 breast cell lines stably transfected with either S100A7 or S100A7 mutated at the Jab1 domain. Structural analysis by three-dimensional protein modeling, immunoprecipitation, and yeast two-hybrid assay and functional analysis using transfected reporter gene and Western blot assays revealed that the in vitro effects of S100A7 on phospho-Akt and the nuclear factor-kappaB pathway are dependent on the Jab1-binding site and the interaction with Jab1. Enhanced epidermal growth factor receptor signaling was also found to correlate with the increased phospho-Akt. Furthermore, the Jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo. We conclude that the S100A7-Jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer.


Subject(s)
Breast Neoplasms/pathology , Calcium-Binding Proteins/physiology , DNA-Binding Proteins/physiology , Peptide Hydrolases/physiology , Transcription Factors/physiology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , COP9 Signalosome Complex , Calcium-Binding Proteins/biosynthesis , Calcium-Binding Proteins/genetics , Cell Adhesion/physiology , Cell Line, Tumor , Cell Survival/physiology , DNA-Binding Proteins/metabolism , Enzyme Activation , Female , Humans , Intracellular Signaling Peptides and Proteins , Mice , Mice, Nude , Mutation , NF-kappa B/metabolism , Neoplasm Transplantation , Peptide Hydrolases/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , S100 Calcium Binding Protein A7 , S100 Proteins , Transcription Factors/metabolism , Transplantation, Heterologous
10.
Bioorg Med Chem Lett ; 14(23): 5919-24, 2004 Dec 06.
Article in English | MEDLINE | ID: mdl-15501069

ABSTRACT

We have recently reported the synthesis of a series of original 17beta-estradiol-linked platinum(II) hybrid molecules. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human uterine and ovarian cancers. The hybrid molecules present higher affinity than that of 17beta-estradiol for the estrogen receptor alpha (ERalpha). The cytotoxicity and the affinity of the hybrid molecules are explained using molecular modeling analysis. This study further confirms that the derivatives made of a 2-(2'-aminoethyl)pyridine ligand displayed superior activity against the cell lines particularly when the connecting arm is 8-10 carbon atoms long. Molecular modeling shows that a long side chain can facilitate the access of the platinum(II) moiety to DNA. The novel compounds also prove to be moderately cytotoxic against platinum resistant endometrial and ovarian cancer cell lines.


Subject(s)
Estradiol/chemistry , Models, Molecular , Ovarian Neoplasms/drug therapy , Platinum Compounds/chemistry , Uterine Neoplasms/drug therapy , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Estradiol/metabolism , Estradiol/therapeutic use , Female , Humans , Ovarian Neoplasms/metabolism , Platinum Compounds/metabolism , Platinum Compounds/therapeutic use , Protein Binding/physiology , Uterine Neoplasms/metabolism
11.
Bioorg Med Chem Lett ; 13(22): 3927-31, 2003 Nov 17.
Article in English | MEDLINE | ID: mdl-14592477

ABSTRACT

The synthesis of a novel series of 17beta-estradiol-linked platinum(II) complexes is described. The new molecules are linked with an alkyl chain at position 16alpha of the steroid nucleus and bear a 16beta-hydroxymethyl side chain. They are made from estrone in five chemical steps with an overall yield exceeding 28%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast cancers. The derivatives incorporating a 2-(2'-aminoethyl)pyridine ligand displayed good activity against the cell lines particularly when the connecting arm is 10 carbon atoms long.


Subject(s)
Antineoplastic Agents/chemical synthesis , Estradiol/chemical synthesis , Estradiol/toxicity , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/toxicity , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Breast Neoplasms , Cell Line, Tumor , Cell Survival/drug effects , Estradiol/analogs & derivatives , Female , Humans , Molecular Conformation , Organoplatinum Compounds/chemistry
12.
Inorg Chem ; 35(11): 3117-3125, 1996 May 22.
Article in English | MEDLINE | ID: mdl-11666507

ABSTRACT

Macrocyclic dicopper(II) complexes derived from 2,6-di(R)formylphenols and various linking diamines are surveyed and their magnetic and structural properties assessed. For those systems with "flat" dinuclear centers and no electronic perturbations associated with electron-withdrawing ligands or ligand groups, the complexes exhibit a "straight-line" relationship between exchange integral and phenoxide bridge angle. Within the angle range 98.8-104.7 degrees, 11 complexes are included with -2J in the range 689-902 cm(-)(1). When electron-withdrawing species are present, either as ligands or as groups bound to the macrocycle itself, considerable suppression of the antiferromagnetic exchange component is observed. Single-crystal X-ray diffraction studies are reported for three complexes. [Cu(2)(L1)(H(2)O)(2)]F(2)(CH(3)OH)(2) (1) crystallized in the triclinic system, space group P&onemacr;, with a = 8.1878(5) Å, b = 9.0346(7) Å, c = 10.4048(7) Å, alpha = 103.672(6) degrees, beta = 101.163(5) degrees, gamma = 104.017(5) degrees, and Z = 1. [Cu(2)(L2)Cl(2)] [Cu(2)(L2) (H(2)O)(2)]Cl(ClO(4)).5.5H(2)O (2) crystallized in the monoclinic system, space group P2(1)/n, with a = 14.4305(5) Å, b = 24.3149(8) Å, c = 18.6584(8) Å, beta = 111.282(3) degrees, and Z = 4. [Cu(2)(L3)(H(2)O)(2)](BF(4))(2) (3) crystallized in the triclinic system, space group P&onemacr;, with a = 8.6127(4) Å, b = 8.6321(7) Å, c = 10.8430(10) Å, a = 74.390(10) degrees, beta = 86.050(10) degrees, gamma = 76.350(10) degrees, and Z = 2. Square pyramidal copper ion stereochemistries are observed in all cases, with axially coordinated halogens or water molecules. Strong antiferromagnetic exchange is observed for all complexes (-2J = 784(8) cm(-)(1), Cu-O-Cu 103.65(10) degrees (1); -2J = 801(11) cm(-)(1), Cu-O-Cu 102.4(3), 107.5(3), 102.9(3), 106.1(3) degrees (2); -2J = 689(3) cm(-)(1), Cu-O-Cu 98.8(4) degrees (3)). The presence of electron-withdrawing CN groups on the periphery of the macrocyclic ligand leads to substantially reduced antiferromagnetic exchange.

13.
Postgrad Med ; 58(2): 54-62, 1975 Aug.
Article in English | MEDLINE | ID: mdl-27414427

ABSTRACT

Echocardiography occupies a unique place as an investigative tool in cardiology. This introduction to the technique reviews the basic principles and outlines the diagnosis of common cardiac lesions. Being entirely noninvasive, echocardiography can be repeated to ascertain the severity and observe the progression of cardiac lesions.

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