Synthesis of (R)-3,4-dihydro-2H-pyran-2-carboxaldehyde: application to the synthesis of potent adenosine A(2A) and A(3) receptor agonist.

Synthesis of potent adenosine A(2A) and A(3) receptor agonist from the modification of adenosine-5'-N-ethylcarboxamide (NECA) has been reported. Diastereoisomer possessing an (R) 3,4-dihydro-2H-pyranyl (DHP) moiety exhibited the highest affinity at the A(2A) and A(3) receptors. The key steps involve the synthesis of (R)-3,4-dihydro-2H-pyran-2-carboxaldehyde (7), which was obtained through the enzyme catalyzed kinetic resolution of (±)-2-acetoxymethyl-3,4-dihydro-2H-pyran (5).

Structure-activity relationship study of tricyclic necroptosis inhibitors.

Necroptosis is a regulated caspase-independent cell death mechanism that can be induced in multiple cell types and is characterized by morphological features resembling necrosis. Here we describe a series of tricyclic heterocycles (i.e., 3-phenyl-3,3a,4,5-tetrahydro-2H-benz[g]indazoles, 3-phenyl-2,3,3a,4-tetrahydro[1]benzopyrano[4,3-c]pyrazoles, 3-phenyl-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazoles, and 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro[1]benzothiopyrano[4,3-c]pyrazoles], collectively termed Nec-3, that can potently inhibit necroptosis. For example, compounds 8, 22, 41, 53, and 55 inhibit necroptosis in an FADD-deficient variant of human Jurkat T cells treated for 24 h with TNF-alpha with EC50 values in the range 0.15-0.29 microM. Distinct from the previously described series of hydantoin-containing indole derivatives (Nec-1), the Nec-3 series exhibits specificity in inhibiting TNF-alpha-induced necroptosis. A structure-activity relationship (SAR) study revealed that the (3R,3aR)-rel-diastereomers were more active than the (3R,3aS)-rel-diastereomers for all four ring systems. Introduction of fluorine or methoxy to the 8-position of the tricyclic ring and a methoxy to the 4-position of the pendent phenyl ring increased activity. Amides at the 2-position of the tricyclic ring were best. The Nec-3 series provides new tools for elucidating caspase-independent cell death pathways and potentially lead compounds for therapeutic development.

Discovery of potent poly(ADP-ribose) polymerase-1 inhibitors from the modification of indeno[1,2-c]isoquinolinone.

Novel indeno[1,2-c]isoquinolinone derivatives were synthesized and evaluated as inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). These potent nonmutagenic PARP-1 inhibitors possess an additional five-membered ring between the B and C rings of 6(5H)-phenanthridinone. The most potent PARP-1 inhibitors were obtained from the substitution of the D ring at the C-9 position, in particular sulfonamide and N-acyl analogues (6 and 11). The 9-sulfonamide analogues 11a and 12a exhibited IC(50) values of 1 and 10 nM, respectively.

Facile and convenient syntheses of 6,11-dihydro-5H-indeno[1,2-c]isoquinolin- 5-ones and 6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-one.

[reaction: see text] The synthesis of 6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-ones from the base-promoted condensation reaction of homophthalic anhydride and 2-(bromomethyl)-benzonitrile and a convenient method for the synthesis of indolo[3,2-c]isoquinolinones are described.

2-(N-acyl) and 2-N-acyl-N(6)-substituted analogues of adenosine and their affinity at the human adenosine receptors.

A series of 2-(N-acyl) and 2-(N-acyl)-N(6)-alkyladenosine analogues have been synthesized from the intermediate 2-amino-6-chloroadenosine derivatives (2b and 7) and evaluated for their affinity at the human A(1), A(2A), and A(3) receptors. We found that 2-(N-acyl) derivatives of adenosine showed relatively low affinity at A(2A) and A(3) receptors, while the N(6)-cyclopentyl substituent in 4h and 4i induced high potency [A(1) (K(i))=20.7 and 31.8 nM respectively] at the A(1) receptor and resulted therefore in increased selectivity for this subtype. The general synthetic methods and their binding studies are presented herein.

The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).

A series of novel 4-(N-acyl)-2,3-dihydro-1H-isoindol-1-ones have been prepared from methyl-3-nitro-2-methylbenzoate and linked through various spacers to the adenosine derivatives 11 and 12. We found that potent inhibition of poly(ADP-ribose)polymerase-1 (PARP-1) was achieved when isoindolinone was linked to adenosine by a spacer group of a specific length. Introduction of piperazine and succinyl linkers between the isoindolinone and adenosine core structures resulted in highly potent compounds 8a and 10b, which showed IC(50) values of 45 and 100 nM, respectively.

Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl, and 7,10-diacyl analogues of paclitaxel (taxol) using solid phase synthesis.

A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a-7e and 9a-9u) have been synthesized using a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel analogues have been prepared by conventional chemistry. In the first series, 10-deacetylpaclitaxel (4) was linked through its 2'-hydroxyl group using 1% polystyrene-divinyl benzene resin functionalized with butyldiethylsilane linker (PS-DES) and then acylated at the C-10 hydroxyl group with various anhydrides and dialkyl dicarbonates in the presence of CeCl(3). The resin-bound C-10 acylated paclitaxel derivatives (6a-6e) were then treated with various carboxylic acids in the presence of 1,3-diisopropylcarbodiimide in toluene to provide polymer-supported 7,10-diacylpaclitaxels (8a-8u). These 7-acyl- and 7,10-diacylpaclitaxels (6a-6e and 8a-8u) were cleaved from the resin to give the 24 paclitaxel analogues 7a-7e and 9a-9u. Nine 7-acyl-10-deacetylpaclitaxel analogues were also prepared by conventional chemistry. Methodology to determine the tubulin-assembly activity of compounds prepared in small quantities by a combinatorial approach has been developed, and four analogues with improved tubulin-assembly activity as compared with paclitaxel were found, together with two analogues with improved cytotoxicity.

Poly(ADP-Ribose) polymerase inhibition reduces reperfusion injury after heart transplantation.

The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure-volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.

Synthesis and Biological Evaluation of 1-Deoxypaclitaxel Analogues.

The naturally occurring taxoid baccatin VI has been converted to various 1-deoxypaclitaxel derivatives by selective deacylation followed by attachment of the C-13 side chain. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with activity comparable to that of paclitaxel were discovered. It thus appears that the 1-hydroxyl group is not necessary for the activity of paclitaxel.