Oscar Moradei

Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.

4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors.

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.

Simple Stereocontrolled Synthesis of Methyl 2-Deoxy-d-erythro-hexopyranosid-4-uloses, Thromboxane B2 (TXB2) Precursors, from d-Galactose

Abstract The stereospecific synthesis of methyl 3-O-benzoyl-6-O-(tert-butyldiphenylsilyl)-2-deoxy-α-d-erythro-hexopyranosid-4-ulose (5) - a Thromboxane B2 (TXB2) precursor -starting from D-galactose is described. Facile and established methods including selective benzoylation, oxidation-elimination and a stereocontrolled hydrogenation (Pd/charcoal) were employed effectively.

SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.

Synthesis of Furanose Glycosides of Abequose (3, 6-Dideoxy-D-Xylo-Hexose)

ABSTRACT Hydrogenolysis of 2,3,5-tri-O-benzoyl-6-O-trityl-D-galactono-1,4-lactone (2) gave the corresponding 3-deoxy-D-xylo-hexono-1,4-lactone derivative (3), which on treatment with HBr in acetic acid afforded 2,5-di-O-benzoyl-6-bromo-3,6-dideoxy-D-xylo-hexono 1,4-lactone (4). Hydrogenation of 4 led to 3,6-dideoxy-D-xylo-hexono-1,4-lactone dibenzoate (6). The overall yield of 6 from D-galactono-1, 4-lactone (1) was about 59%. Alternatively, compound 6 was prepared (67% overall yield from 1) by hydrogenolysis of 6-bromo-6-deoxy-D-galactono-1,4-lactone tribenzoate (5), obtained by treatment of 2 with HBr in dry dichloromethane. Diisoamylborane reduction of 6 gave an anomeric mixture of 2,5-di-O-benzoyl-3,6-dideoxy-α, β-D-xylo-hexofuranose (7), which on O-debenzoylation afforded 3,6-dideoxy-D-xylo-hexose (abequose, 8) whose tautomeric equilibrium was studied by 13C NMR spectroscopy. Acetylation of 7 gave the 1-O-acetyl derivative (9) mainly in the β anomeric configuration. Tin (IV) chloride promoted glycosy...

Amine-Induced Deacylation of Carbohydrate Derivatives Under Anhydrous Conditions

Abstract Methanolysis of acylated carbohydrate derivatives was effectively performed using tertiary amines in the absence of water at room temperature. The reaction was performed with acetylated and benzoylated alditols, aldoses, lactones, orthoesters, glycosides, and disaccharides. N-methyl-pyrrolidine proved to be especially suitable for synthetic purposes and deacylated compounds were obtained in excellent yields. The mild conditions employed and the minimum work-up needed make this method appropriate for the deacylation of labile compounds.

Catalytic Hydrogenation of Phosphate Enol Esters Present in Branched Chain Dienepyranosides in a Route to Thromboxane Analogs from D-Galactose

ABSTRACT Branched-chain conjugated dienepyranosides including vinyl phosphate esters were subjected to catalytic hydrogenation under different conditions. Heterogeneous catalysts led to isomerization products that were resistant to further hydrogenation. On the other hand, under homogeneous conditions, complete stereoselective hydrogenation was achieved. Methyl 2,4-dideoxy-3-O-diethoxyphosphoryl-4-C-[(methoxycarbonyl)methyl]-α-D-ribo-hexopyranoside (6b), a potential precursor of thromboxane analogs, was obtained.

Anomalous Horner-Wadsworth-Emmons reactions on 3,4-enuloses

Abstract Pyranosic enuloses were subjected to Horner-Wadsworth-Emmons (HWE) conditions using the enolate of dimethyl(methoxycarbonyl)methyl phosphonate and its ethyl analogue. 3-O-Phosphorylation of the products as well as an unusual stereoespecificity were observed. A mechanism involving a phosphonate-phosphate like rearrangement through a five member intermediate followed by benzoate elimination is proposed.

Studies on the Regioselectivity of Horner-Wadsworth-Emmons (Hwe) Reactions on 3,4-Enuloses. Further Evidence of Phosphonate-Phosphate Rearrangements Through Five Membered Cyclic Intermediates.

ABSTRACT The Horner-Wadsworth-Emmons (HWE) reaction was performed on methyl 3,6-di-O-benzoyl-2-deoxy-α-D-glycero-hex-2-enopyranosid-4-ulose (1) with the potassium enolates of dimethyl [(methoxycarbonyl)methyl]phosphonate (2) or diethyl [(ethoxycarbonyl) methyl]phosphonate (3) under different conditions (metallic cation and solvent) in order to study regio- and stereochemical aspects of the reaction. In the presence of lithium ions, no reaction took place. When sodium enolates were employed, 1,2-addition was the main reaction in chelating solvents, whereas the 1,4-adduct is favoured in the less polar, non chelating toluene. Only 1,2-addition was observed with potassium enolates. Evidence of phosphonate-phosphate rearrangements through five membered cyclic intermediates is described.

Abstract 2437: Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates

Co-activator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers including AML (1) and breast (2), prostate (3), lung (4) and colorectal (5) carcinomas. CARM1 is known to methylate H3 histones and non-histone substrates including p300/CBP, AIB1/SRC-3 and PABP1 (6). To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors (7), but no ternary structures with nucleotide and peptide substrate have been reported. Here, the crystal structures of human CARM1 with the SAM mimic sinefungin (SFG) and three different peptide sequences from histone H3 and PAPB1 are presented, and both non-methylated and singly-methylated arginine residues are exemplified. Extensive interactions are seen with residues Glu266, Glu257, and His414 and the substrate arginine side chain. Two key hydrogen bonds are made by the side chain of Asn161 with the backbone carbonyl of the P’1 peptide residue and the backbone NH of the P’3 peptide residue. The carbonyl of the P1 peptide residue engages the protein through water mediated hydrogen bonds. These structures show how the CARM1 binding site is capable of accommodating a variety of peptide sequences. Comparisons to known CARM1 complexes with small molecules provide additional insights into inhibitor design. 1. Vu, L. P. et al, PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep 2013, 5 (6), 1625-38. 2. Al-Dhaheri, M. et al, CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res 2011, 71 (6), 2118-28. 3. Kim, Y. R. et al, Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 2010, 10, 197. 4. Elakoum, R. et al, CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie 2014, 97, 210-8. 5. Ou, C. Y. et al, A coactivator role of CARM1 in the dysregulation of beta-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res 2011, 9 (5), 660-70. 6. Bedford M.T.; Clarke S.G. Protein arginine methylation in mammals: who, what, and why. Mol Cell 2009, 33, 1-13. 7. Sack, J.S et al, Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. Biochem J 2011, 436, 331-9. Citation Format: Ann Boriack-Sjodin, Lei Jin, Suzanne L. Jacques, Allison Drew, Margaret Porter Scott, Scott Ribich, Oscar Moradei. Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2437. doi:10.1158/1538-7445.AM2015-2437