An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity.

Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.

[1]  J. Milner,et al.  Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency , 2006, Oncogene.

[2]  John Calvin Reed,et al.  Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt , 2006, Oncogene.

[3]  C. Qu,et al.  Effects of a Leukemia-associated Gain-of-Function Mutation of SHP-2 Phosphatase on Interleukin-3 Signaling* , 2006, Journal of Biological Chemistry.

[4]  E. Tchilian,et al.  Altered CD45 expression and disease. , 2006, Trends in immunology.

[5]  R. Xu,et al.  [Overexpression of Shp-2 is associated with the unlimited growth and apoptosis resistance of p210 bcr-abl-mediated chronic myeloid leukemia]. , 2005, Zhonghua yi xue za zhi.

[6]  M. Dawson,et al.  Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation. , 2005, Cancer research.

[7]  J. Nicolas,et al.  SHP represses transcriptional activity via recruitment of histone deacetylases. , 2005, Biochemistry.

[8]  Y. Pak,et al.  Negative cross-talk between Nur77 and small heterodimer partner and its role in apoptotic cell death of hepatoma cells. , 2005, Molecular endocrinology.

[9]  M. Jeffers,et al.  Anti-angiogenic therapy as a cancer treatment paradigm. , 2005, Current medicinal chemistry. Anti-cancer agents.

[10]  E. Papadimitriou,et al.  Effects of retinoic acid steroidal analogs on human leukemic HL60 cell proliferation in vitro and on angiogenesis in vivo , 2005, Anti-cancer drugs.

[11]  M. Loh,et al.  Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. , 2004, Blood.

[12]  A. Rishi,et al.  Antagonist analogue of 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest. , 2004, Journal of medicinal chemistry.

[13]  O. Wiest,et al.  Inhibition studies with rationally designed inhibitors of the human low molecular weight protein tyrosine phosphatase. , 2004, Bioorganic & medicinal chemistry.

[14]  M. Blagosklonny.  Prospective strategies to enforce selectively cell death in cancer cells , 2004, Oncogene.

[15]  Ying Huang,et al.  Apoptosis signaling by the novel compound 3-Cl-AHPC involves increased EGFR proteolysis and accompanying decreased phosphatidylinositol 3-kinase and AKT kinase activities , 2004, Oncogene.

[16]  L. Wistrand,et al.  Synthesis of fused tetrazole derivatives via a tandem cycloaddition and N-allylation reaction and parallel synthesis of fused tetrazole amines. , 2004, The Journal of organic chemistry.

[17]  M. Pfahl,et al.  Retinoid targets for apoptosis induction , 2003, Oncogene.

[18]  R. Mohammad,et al.  Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog. , 2003, Blood.

[19]  Ding-Yah Yang.  4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. , 2003, Drug news & perspectives.

[20]  Daniel Delorme,et al.  Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. , 2003, Journal of medicinal chemistry.

[21]  G. Chen,et al.  Novel 3-phenylprop-2-ynylamines as inhibitors of mammalian squalene epoxidase. , 2003, Organic & biomolecular chemistry.

[22]  J. Gustafsson,et al.  Glucocorticoid Signaling Is Perturbed by the Atypical Orphan Receptor and Corepressor SHP* , 2002, The Journal of Biological Chemistry.

[23]  F. Palacios,et al.  Synthesis of Quinolinylphosphane Oxides and -phosphonates from N-Arylimines Derived from Phosphane Oxides and Phosphonates , 2002 .

[24]  R. Mohammad,et al.  Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog. , 2002, Blood.

[25]  J. Auwerx,et al.  The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. , 2002, Molecular endocrinology.

[26]  B. Cho,et al.  Synthesis and nonlinear optical properties of 1,3,5-methoxy-2,4,6-tris(styryl)benzene derivatives. , 2002, Organic letters.

[27]  M. Dawson,et al.  Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid. , 2002, Current medicinal chemistry.

[28]  M. Deinzer,et al.  Mass-spectrometric analysis of agonist-induced retinoic acid receptor γ conformational change , 2002 .

[29]  W. Guida,et al.  Accurate Prediction of Acidity Constants in Aqueous Solution via Density Functional Theory and Self-Consistent Reaction Field Methods , 2002 .

[30]  M. Dawson,et al.  Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. , 2001, Cancer research.

[31]  C. Klinge,et al.  Short heterodimer partner (SHP) orphan nuclear receptor inhibits the transcriptional activity of aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT). , 2001, Archives of biochemistry and biophysics.

[32]  J. Capone,et al.  The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor α-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal β-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase , 2001, Molecular and Cellular Endocrinology.

[33]  M. Widschwendter,et al.  Epigenetic Downregulation of the Retinoic Acid Receptor-β2 Gene in Breast Cancer , 2001, Journal of Mammary Gland Biology and Neoplasia.

[34]  Rossi,et al.  Strong bicyclic guanidine base-promoted wittig and horner-wadsworth-emmons reactions , 2000, Organic letters.

[35]  G. Loew,et al.  Development and assessment of a 3D pharmacophore for ligand recognition of BDZR/GABAA receptors initiating the anxiolytic response. , 2000, Bioorganic & medicinal chemistry.

[36]  John Calvin Reed,et al.  Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. , 2000, Science.

[37]  T. Delorey,et al.  Determinants of recognition of ligands binding to benzodiazepine receptor/GABA(A) receptors initiating sedation. , 2000, European journal of pharmacology.

[38]  D. Moras,et al.  Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Rishi,et al.  Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis , 2000, International journal of cancer.

[40]  K. Pienta,et al.  Galectin-3 induces endothelial cell morphogenesis and angiogenesis. , 2000, The American journal of pathology.

[41]  S. Kato,et al.  Altered expression of CD45 isoforms in differentiation of acute myeloid leukemia , 1999, American journal of hematology.

[42]  M. Sheikh,et al.  Activation of the p38 and JNK/SAPK mitogen-activated protein kinase pathways during apoptosis is mediated by a novel retinoid. , 1999, Experimental cell research.

[43]  A. Itai,et al.  Novel thiazolidinedione derivatives with retinoid synergistic activity. , 1998, Biological & pharmaceutical bulletin.

[44]  D. Moore,et al.  Novel receptor interaction and repression domains in the orphan receptor SHP , 1997, Molecular and cellular biology.

[45]  R. Nagaraj,et al.  Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct. , 1997, Archives of biochemistry and biophysics.

[46]  H. Broxmeyer,et al.  A Coiled-coil Tetramerization Domain of BCR-ABL Is Essential for the Interactions of SH2-containing Signal Transduction Molecules* , 1996, The Journal of Biological Chemistry.

[47]  X. -. Li,et al.  Posttranscriptional regulation of p21WAF1/CIP1 expression in human breast carcinoma cells. , 1996, Cancer research.

[48]  R. Lotan.  Retinoids and their receptors in modulation of differentiation, development, and prevention of head and neck cancers. , 1996, Anticancer research.

[49]  B. Shroot,et al.  Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. , 1995, Journal of medicinal chemistry.

[50]  Jean-Paul Renaud,et al.  Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid , 1995, Nature.

[51]  Norio Miyaura,et al.  Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds , 1995 .

[52]  M. Sheikh,et al.  p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. , 1995, Oncogene.

[53]  T. Chakraborty,et al.  An expeditious approach for the synthesis of β-hydroxy aryl α-amino acids present in vancomycin , 1994 .

[54]  S. Wittenberger,et al.  Dialkyltin oxide mediated addition of trimethylsilyl azide to nitriles. A novel preparation of 5-substituted tetrazols , 1993 .

[55]  K. Robertson,et al.  Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity. , 1992, Blood.

[56]  B. Shroot,et al.  Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. , 1992, Biochemical and biophysical research communications.

[57]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[58]  R. Richardson,et al.  Chemical modification by pyridoxal 5'-phosphate and cyclohexane-1,2-dione indicates that Lys-7 and Arg-10 are involved in the p2 phosphate-binding subsite of bovine pancreatic ribonuclease A. , 1990, The Biochemical journal.

[59]  Vishwanatha Somayaji,et al.  Vinylic organoboranes. 13. A convenient stereospecific synthesis of (Z)-1-halo-1-alkenes from 1-alkynes via (E)-1-alkenylborane derivatives with halogens , 1989 .

[60]  M. Dawson,et al.  Synthesis and pharmacological activity of 6-[(E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethen-1-yl]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids. , 1983, Journal of medicinal chemistry.

[61]  C. Thorpe,et al.  Modification of an arginine residue in pig kidney general acyl-coenzyme A dehydrogenase by cyclohexane-1,2-dione. , 1982, The Biochemical journal.

[62]  M. Sporn,et al.  Structure-activity relationships of retinoids in hamster tracheal organ culture. , 1980, Cancer research.

[63]  A. Verma,et al.  Correlation of the inhibition by retinoids of tumor promoter-induced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion. , 1979, Cancer research.

[64]  A. Mancuso,et al.  Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide "activated" by oxalyl chloride , 1978 .

[65]  M. Doyle,et al.  Alkyl Nitrite-Metal Halide Deamination Reactions. 2. Substitutive Deamination of Arylamines by Alkyl Nitrites and Copper(II) Halides. A Direct and Remarkably Efficient Conversion of Arylamines to Aryl Halides , 1977 .

[66]  R. Mueller,et al.  Prostaglandins. IV. A synthesis of F-type prostaglandins. A total synthesis of prostaglandin F 1 . , 1972, The Journal of organic chemistry.

[67]  G. Scuseria,et al.  Gaussian 03, Revision E.01. , 2007 .

[68]  D. Moore,et al.  Adamantyl-substituted retinoid-related molecules bind small heterodimer partner and modulate the Sin3A repressor. , 2007, Cancer research.

[69]  Y. Hashimoto,et al.  Polyenylidene thiazolidinedione derivatives with retinoidal activities. , 1997, Chemical & pharmaceutical bulletin.