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1.
J Med Chem ; 44(17): 2719-34, 2001 Aug 16.
Article in English | MEDLINE | ID: mdl-11495584

ABSTRACT

A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.


Subject(s)
Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Quinazolines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Blotting, Western , Cell Division/drug effects , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Fluorometry , Glutathione/chemistry , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Nude , Models, Molecular , Phosphorylation , Precipitin Tests , Quinazolines/chemistry , Quinazolines/pharmacology , Transplantation, Heterologous , Tumor Cells, Cultured
2.
J Med Chem ; 43(17): 3244-56, 2000 Aug 24.
Article in English | MEDLINE | ID: mdl-10966743

ABSTRACT

The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.


Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Nitriles/chemical synthesis , Quinazolines/chemical synthesis , Quinolines/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fluorometry , Humans , Inhibitory Concentration 50 , Models, Molecular , Nitriles/chemistry , Nitriles/pharmacology , Phosphorylation , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
3.
J Med Chem ; 43(6): 1062-70, 2000 Mar 23.
Article in English | MEDLINE | ID: mdl-10737739

ABSTRACT

Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes. This enzyme catalyzes the reduction of glucose to sorbitol using nicotinamide adenine dinucleotide phosphate as an essential cofactor. AR has been localized at the sites of tissue damage, and inhibitors of this enzyme prevent the development of neuropathy, nephropathy, retinopathy, and cataract formation in animal models of diabetes. The crystal structure of AR complexed with zopolrestat, a potent inhibitor of AR, has been described.(1) We have generated a model of the AR-inhibitor complex based on the reported Calpha coordinates of the protein and results of a structure-activity relationship study using four structurally distinct classes of inhibitors, recombinant human AR, and four single-site-directed mutants of this enzyme. The effects of the site-directed mutations on residues within the active site of the enzyme were evaluated by average interaction energy calculations and by calculations of carbon atom surface area changes. These values correlated well with the IC(50) values for zopolrestat with the wild-type and mutant enzymes, validating the model. On the basis of the zopolrestat-binding model, we have proposed binding models for 10 other AR inhibitors. Our models have enabled us to gain a qualitative understanding of the binding domains of the enzyme and how different inhibitors impact the size and shape of the binding site.


Subject(s)
Aldehyde Reductase/chemistry , Enzyme Inhibitors/chemistry , Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/genetics , Benzothiazoles , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Mutagenesis, Site-Directed , Phthalazines/chemistry , Recombinant Proteins/chemistry , Structure-Activity Relationship , Thiazoles/chemistry
4.
Biochem Pharmacol ; 57(8): 917-25, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10086326

ABSTRACT

It has been shown previously that 4-anilino quinazolines compete with the ability of ATP to bind the epidermal growth factor receptor (EGF-R), inhibit EGF-stimulated autophosphorylation of tyrosine residues in EGF-R, and block EGF-mediated growth. Since millimolar concentrations of ATP in cells could reduce the efficacy of 4-anilino quinazolines in cells and the activity of these compounds would not be sustained once they were removed from the body, we reasoned that irreversible inhibitors of EGF-R might improve the activity of this series of compounds in animals. Molecular modeling of the EGF-R kinase domain was used to design irreversible inhibitors. We herein describe one such inhibitor: N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]2-butynamide, known as CL-387,785. This compound covalently bound to EGF-R. It also specifically inhibited kinase activity of the protein (IC50 = 370+/-120 pM), blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2, and profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily). We conclude that CL-387,785 is useful for studying the interaction of small molecules with EGF-R and may have clinical utility.


Subject(s)
Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Cell Division/drug effects , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , ErbB Receptors/metabolism , Female , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Phosphorylation/drug effects , Quinazolines/chemical synthesis , Tumor Cells, Cultured
5.
J Virol ; 73(1): 140-51, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9847316

ABSTRACT

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.


Subject(s)
Antiviral Agents/pharmacology , Cell Fusion/drug effects , Hemagglutinins, Viral/drug effects , Influenza A virus/drug effects , Virus Replication/drug effects , Amantadine/pharmacology , Animals , Cell Line , Cloning, Molecular , Computer Simulation , Hydrogen-Ion Concentration , Influenza A virus/physiology , Models, Molecular , Protein Synthesis Inhibitors/pharmacology , Viral Proteins/biosynthesis
6.
J Comput Aided Mol Des ; 11(5): 447-52, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9385548

ABSTRACT

We present some new ideas for characterizing and comparing large chemical databases. The comparison of the contents of large databases is not trivial since it implies pairwise comparison of hundreds of thousands of compounds. We have developed methods for categorizing compounds into groups or series based on their ring-system content, using precalculated structure-based hashcodes. Two large databases can then be compared by simply comparing their hashcode tables. Furthermore, the number of distinct ring-system combinations can be used as an indicator of database diversity. We also present an independent technique for diversity assessment called the saturation diversity approach. This method is based on picking as many mutually dissimilar compounds as possible from a database or a subset thereof. We show that both methods yield similar results. Since the two methods measure very different properties, this probably says more about the properties of the databases studied than about the methods.


Subject(s)
Databases, Factual , Drug Design , Benzene Derivatives , Hydrocarbons, Cyclic , Molecular Structure
7.
J Chem Inf Comput Sci ; 33(1): 79-85, 1993.
Article in English | MEDLINE | ID: mdl-8440755

ABSTRACT

We present a method for the rapid quantitative shape match between two molecules or a molecule and a template, using atom triplets as descriptors. This technique can be used either as a rapid screen preceding the computationally expensive shape-based docking method developed by Kuntz and co-workers or as a stand-alone method to rank compounds in a large database for their fit to a shape template. The merits and limitations of this method are discussed in detail with examples.


Subject(s)
Drug Design , Binding Sites , Databases, Factual , Ligands , Models, Molecular , Molecular Structure , Software Design
8.
Proc Natl Acad Sci U S A ; 89(18): 8774-8, 1992 Sep 15.
Article in English | MEDLINE | ID: mdl-1528892

ABSTRACT

A sixth member of the mammalian adenylyl cyclase family has been isolated from a canine cardiac cDNA library. This isoform is more highly homologous to type V than to the other adenylyl cyclase types; sequence similarity is apparent even in the transmembrane regions where the greatest divergence among the types exists. Type VI mRNA expression is most abundant in heart and brain; however, unlike type V, a low level of expression is also observed in a variety of other tissues examined. Type VI adenylyl cyclase can be stimulated by NaF, guanosine 5'-[gamma-thio]triphosphate, and forskolin but not by Ca2+/calmodulin, whereas it is inhibited by adenosine and its analogues. Comparison of both their structural and biochemical properties suggests that types V and VI constitute a distinct subgroup of the mammalian adenylyl cyclase family.


Subject(s)
Adenylyl Cyclases/genetics , Adenosine/pharmacology , Adenylyl Cyclases/classification , Adenylyl Cyclases/metabolism , Amino Acid Sequence , Animals , Base Sequence , Calcium/pharmacology , Calmodulin/pharmacology , Cloning, Molecular , Dogs , Gene Expression , Molecular Sequence Data , RNA, Messenger/genetics , Sequence Alignment , Tissue Distribution , Transfection
9.
J Chem Inf Comput Sci ; 31(4): 527-30, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1757507

ABSTRACT

A novel method for generation of chemical structures of potential pharmaceutical interest is presented. Structures are generated by random combination of known fragments and selected by statistical topological techniques. The power of the method lies in the great profusion of candidates generated together with the extremely high selectivity imposed by the techniques of selection.


Subject(s)
Computer Simulation , Drug Design , Models, Chemical , Chemistry, Pharmaceutical , Databases, Factual
10.
Proc Natl Acad Sci U S A ; 86(20): 8165-9, 1989 Oct.
Article in English | MEDLINE | ID: mdl-2813386

ABSTRACT

Pharmacophores, three-dimensional arrangements of chemical groups essential for biological activity, are being proposed in increasing numbers. We have developed a system to search data bases of three-dimensional coordinates for compounds that contain a particular pharmacophore. The coordinates can be derived from experiment (e.g., Cambridge Crystal Database) or be generated from data bases of connection tables (e.g., Cyanamid Laboratories proprietary compounds) via the program CONCORD. We discuss the results of searches for three sample pharmacophores. Two have been proposed by others based on the conformational analysis of active compounds, and one is inferred from the crystal structure of a protein-ligand complex. These examples show that such searches can identify classes of compounds that are structurally different from the compounds from which the pharmacophore was derived but are known to have the appropriate biological activity. Occasionally, the searches find bond "frameworks" in which the important groups are rigidly held in the proper geometry. These may suggest new structural classes for synthesis.


Subject(s)
Antidepressive Agents , Drug Design , Information Systems , Molecular Conformation , Molecular Structure
11.
Science ; 244(4905): 697-9, 1989 May 12.
Article in English | MEDLINE | ID: mdl-2717946

ABSTRACT

Calicheamicin gamma 1I is a recently discovered diyne-ene-containing antitumor antibiotic that cleaves DNA in a double-stranded fashion, a rarity among drugs, at specific sequences. It is proposed that the cutting specificity is due to a combination of the complementarity of the diyne-ene portion of the aglycone with DNA secondary structures and stabilization by association of the thiobenzoate-carbohydrate tail with the minor groove.


Subject(s)
Aminoglycosides , Anti-Bacterial Agents/metabolism , DNA/metabolism , Animals , Antibiotics, Antineoplastic , Base Sequence , Benzoates , Binding Sites , Carbohydrates , Cattle , Computer Simulation , Enediynes , Models, Molecular , Molecular Structure , Nucleic Acid Conformation , Structure-Activity Relationship
12.
J Med Chem ; 29(6): 899-906, 1986 Jun.
Article in English | MEDLINE | ID: mdl-3712379

ABSTRACT

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.


Subject(s)
Molecular Conformation , Receptors, Nicotinic/drug effects , Alkaloids/pharmacology , Azocines , Models, Structural , Nicotine/pharmacology , Parasympathomimetics/pharmacology , Quinolizines , Stereoisomerism , Structure-Activity Relationship , Sympatholytics/pharmacology
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