Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii,Toxoplasma gondii,and Mycobacterium avium dihydrofolate reductase

A concise new route allowing easy access to five previously unreported 2,4-diamino-6-(substituted benzyl)pyrido[2,3-d]pyrimidines (2a-e) was developed, involving condensation of 2,4-dipivaloylamino-5-bromopyrido[2,3-d]pyrimidine (6) with an organozinc halide in the presence of a catalytic amount of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH(2)Cl(2), followed by removal of the pivaloyl groups with base. Also prepared via a scheme based on the Taylor ring expansion/ring annulation synthesis were three heretofore undescribed 2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium, three examples of opportunistic pathogens to which AIDS patients are highly vulnerable because of their immunocompromised state. For comparison, 13 previously untested 2,4-diamino-6-(substituted benzyl)quinazolines (17a-m) were also evaluated as inhibitors of these enzymes, as well as the enzyme from rat liver. None of the quinazolines or pyridopyrimidines tested was more potent against the P. carinii enzyme than the structurally related reference compound piritrexim (1), and none showed selectivity for the P. carinii enzyme over the rat enzyme. One of the pyridopyrimidines (2c) showed 10-fold selectivity for T. gondii versus rat DHFR, and two of them (2b, 2c) showed selectivity for the M. avium enzyme. However, this gain in species selectivity was achieved at the cost of decreased in potency, as has been noted with many other lipophilic DHFR inhibitors.     

Glucose-6-phosphatase catalytic enzyme inhibitors: synthesis and in vitro evaluation of novel 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines

The discovery of the first class of potent glucose-6-phosphatase catalytic site inhibitors, substituted 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines, is described. Optimisation of this series involved solution phase combinatorial synthesis and very potent compounds were prepared with IC50 values down to 140 nM. The structure activity relationship (SAR) of these compounds indicates that: a tetrahydrothieno[3,2-c]pyridine core ring system and the isomeric [2,3-c] system are equipotent and much better than the corresponding benzo analogue, 1,2,3,4-tetrahydro-isoquinoline. The 4-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a phenyl group, optionally substituted with a lipophilic 4-substituent, such as trifluoromethoxy or chloro. The 5-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a substituted benzoyl; anisoyl and (E)-3-furan-3-ylacryloyl are the best of the investigated groups. Substitution in the benzoyl ortho position seems to be forbidden, whereas substitution in the meta position is tolerated only if a methoxy para substituent is present. These SAR findings were parallel to those obtained in the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine system. Enantioselectivity in enzyme recognition was observed and the activity resided in all cases only in one of the enantiomers.     

Evaluation of the antioxidant properties of diarylamines in the benzo[b]thiophene series by free radical scavenging activity and reducing power

The antioxidant properties of substituted diarylamines in the benzo[b]thiophene series were evaluated by their reducing power and free radical scavenging activity. The results were compared with those of standards: acid ascorbic for the first method and BHA and BHT for the second. For both methods it was possible to establish some structure-activity relationships (SARs) based on the position of the arylamination on the benzo[b]thiophene moiety, the presence of different substituents on the phenyl ring (F, 1 or 2 OMe) and on the thiophene ring (H, CO(2)Et, CO(2)H).     

Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK(1) antagonists

Novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones were designed and prepared as part of a search for NK1 antagonists. Structure-activity relationship studies indicated that the conformational restriction resulting from the incorporation of an oxazocine ring and the presence of a terminal heteroatom on the cyclic amino group at the C-9 position play important roles in NK1, receptor recognition.     

Substituted 2-(3′,4′,5′-trimethoxybenzoyl)-benzo[b]thiophene derivatives as potent tubulin polymerization inhibitors

The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3′,4′,5′-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2–M phase of the cell cycle and induced apoptosis.In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure–activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2–M phase via microtubule depolymerization.     

Bicyclo[3,2,1]octanoid,neolignans from Aniba simulans

Six bicyclo[3,2,1]octanoid neolignans, isolated from the benzene extract of Aniba simulans Allen (Lauraceae) trunk wood, are shown to derive from two basic structures: 1-allyl-8-hydroxy-6-(3′-methoxy-4′,5′-methylenedioxyphenyl)-7-methyl-3-oxobicyclo[3,2,1]octane, substituted by 4-hydroxy, 4-hydroxy-5-methoxy, 4-methoxy or 4,5-dimethoxy groups; and 1-allyl-8-hydroxy-6-(3′-methoxy-4′,5′-methylenedioxyphenyl)-7-methyl-4-oxobicyclo[3,2,1]oct-2-ene, substituted by 3-hydroxy or 3-hydroxy-5-methoxy groups. The structural proposals are based on spectral data, interconversions synthesis of a derivative from the known (2R,3S,3aS)-3a-allyl-5-methoxy-2-(3′-methoxy,4′,5′-methylenedioxyphenyl)-3-methyl-2,3,3a,6-tetrahydro-6-oxobenzofuran.     

An efficient alternative route to 3,6-disubstituted-furo[2,3-d]pyrimidin-2-one analogues

Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2,3-d]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2,3-d]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrinmidin-2-one analogues.     

2-Aminothiophene-3-carboxylates and carboxamides as adenosine A1 receptor allosteric enhancers

Three series of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene and 2-amino-5,6,7,8-tetrahydrocyclohepta[b]thiophenes with 3-carboxylates and carboxamides have been prepared using the Gewald synthesis and evaluated as A(1)AR allosteric enhancers. The structure-activity relationships of these classes of compound are described. A number of compounds, notably 7b, are more potent and efficacious than PD81,723 (1).     

8-Phosphorus substituted isosteres of purine and deazapurines.

Synthesis of 8-phosphorus substituted isosteres of purine [pyrimidino (4,5-d)-1,3,2-diazaphosphole], 1-deazapurine [pyridino (2,3-d)-1,3,2-diazaphosphole] and 3-deazapurine [pyridino (4,5-d)-1,3,2-diazaphosphole] has been achieved by the reaction of equimolar amounts of triphenylphosphite and 4,5-diaminopyrimidine, 2,3-diaminopyridine and 3,4-diaminopyridine, respectively. These compounds hydrolyzed (cleavage of the phosphorus-nitrogen bounds) in aqueous solutions to provide the corresponding diaminopyrimidine or diaminopyridines. These three new basic ring systems constitute the first reported synthesis of purines in which ring carbon atom is substituted with a phosphorus atom. 8-Phosphorus substituted purine at a concentration of 4 X 10(-4)M caused a 50% inhibition in the growth of leukemia L1210 cells in culture. The biochemical rationale for the synthesis of these compounds is discussed.     

Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.     

Transformations of six isomers of dimethylbenzothiophene by three Pseudomonas strains

Dimethylbenzothiophenes are among the sulfur heterocycles in petroleum that are known to be degraded by microbial activity. Six of the 15 possible isomers of dimethylbenzothiophene were synthesized and used in biotransformation studies with three Pseudomonas isolates that oxidize a variety of condensed thiophenes including methylbenzothiophenes and methyldibenzothiophenes. The isomers of dimethylbenzothiophene were chosen to have a variety of substitution patterns: both methyl groups on the thiophene ring (the 2,3- isomer); a methyl group on each of the rings (the 2,7-, 3,5- and 3,7-isomers); and both methyl groups on the benzene ring (the 4,6- and 4,7- isomers). Each isolate was grown on 1-methylnaphthalene or glucose in the presence of one of the dimethylbenzothiophenes and culture extracts were analyzed to identify nearly 30 sulfur-containing metabolites in total. Sulfoxides and sulfones were commonly found metabolites in culture extracts from the 2,3-, 2,7- and 3,7-isomers, whereas 2,3-diones, 3(2H)-ones and 2(3H)-ones were formed from the 4,6- and 4,7-isomers. High-molecular-weight products, some of which were tentatively identified as tetramethylbenzo[b]naphtho[1,2-d]thiophenes, were detected in the extracts of cultures incubated with 4,6- or 4,7-dimethylbenzothiophene. The methyl groups of all of the isomers, except 4,6-, were oxidized to give hydroxymethyl-methylbenzothiophenes and methylbenzothiophene-carboxylic acids, and these were the only products detected from the oxidation of 3,5-dimethylbenzothiophene.     

Transformations of six isomers of dimethylbenzothiophene by three Pseudomonas strains

Dimethylbenzothiophenes are among the sulfur heterocycles in petroleum that are known to be degraded by microbial activity. Six of the 15 possible isomers of dimethylbenzothiophene were synthesized and used in biotransformation studies with three Pseudomonas isolates that oxidize a variety of condensed thiophenes including methylbenzothiophenes and methyldibenzothiophenes. The isomers of dimethylbenzothiophene were chosen to have a variety of substitution patterns: both methyl groups on the thiophene ring (the 2,3- isomer); a methyl group on each of the rings (the 2,7-, 3,5- and 3,7-isomers); and both methyl groups on the benzene ring (the 4,6- and 4,7- isomers). Each isolate was grown on 1-methylnaphthalene or glucose in the presence of one of the dimethylbenzothiophenes and culture extracts were analyzed to identify nearly 30 sulfur-containing metabolites in total. Sulfoxides and sulfones were commonly found metabolites in culture extracts from the 2,3-, 2,7- and 3,7-isomers, whereas 2,3-diones, 3(2H)-ones and 2(3H)-ones were formed from the 4,6- and 4,7-isomers. High-molecular-weight products, some of which were tentatively identified as tetramethylbenzo[b]naphtho[1,2-d]thiophenes, were detected in the extracts of cultures incubated with 4,6- or 4,7-dimethylbenzothiophene. The methyl groups of all of the isomers, except 4,6-, were oxidized to give hydroxymethyl-methylbenzothiophenes and methylbenzothiophene-carboxylic acids, and these were the only products detected from the oxidation of 3,5-dimethylbenzothiophene.     

Cantharidin analogues: synthesis and evaluation of growth inhibition in a panel of selected tumour cell lines

Diels-Alder addition of furans (furan, furfuryl alcohol, and 3-bromofuran) to maelic anhydride yields three distinct 5,6-dehydronorcantharidins. Hydrogenation of (4,10-dioxatricyclo[5.2.1.0]decane-3,5-dione) (4a), in dry ethanol affords the monoester (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic aid monoethyl ester) (6). Subsequent transesterification affords a series of monoesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monomethyl ester (7)), 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monopropyl ester (8), (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monohexyl ester (9)) and differentially substituted diesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-isopropyl ester) (10), and (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-phenyl ester) (11). Analogues were firstly screened for their ability to inhibit protein phosphatases 1 (PP1) and 2A (PP2A) as the lead compounds cantharidin (1) and norcantharidin (2) are known PP1 and PP2A inhibitors. Only analogues 4a, 6-8 displayed good PP1 and PP2A inhibition (PP1 IC(50)'s=2.0, 2.96, 4.71, and 4.82 microM, respectively; PP2A IC(50)'s=0.2, 0.45, 0.41, and 0.47 microM, respectively). All analogues were also screened for their anti-cancer potential against a panel of tumour cell lines, HL60, L1210, SW480, WiDr, HT29, HCT116, A2780, ADDP, and 143B, producing GI(50) values ranging from 6 microM to >1000 microM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity.     

Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors

Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (±)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH? substituents inhibited human (h) TS (IC?? =0.26-0.8 μM), but not hDHFR. Substitution of the 2-CH? with a 2-NH? increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC?? = 0.09-0.1 μM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.     

Biotransformation of benzothiophene by isopropylbenzene-degrading bacteria.

Isopropylbenzene-degrading bacteria, including Pseudomonas putida RE204, transform benzothiophene to a mixture of compounds. Induced strain RE204 and a number of its Tn5 mutant derivatives were used to accumulate these compounds and their precursors from benzothiophene. These metabolites were subsequently identified by 1H and 13C nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry. When strain RE204 was incubated with benzothiophene, it produced a bright yellow compound, identified as trans-4-[3-hydroxy-2-thienyl]-2-oxobut-3-enoate, formed by the rearrangement of cis-4-(3-keto-2,3-dihydrothienyl)-2-hydroxybuta-2,4-dieno ate, the product of 3-isopropylcatechol-2,3-dioxygenase-catalyzed ring cleavage of 4,5-dihydroxybenzothiophene, as well as 2-mercaptophenylglyoxalate and 2'-mercaptomandelaldehyde. A dihydrodiol dehydrogenase-deficient mutant, strain RE213, converted benzothiophene to cis-4,5-dihydroxy-4,5-dihydrobenzothiophene and 2'-mercaptomandelaldehyde; neither trans-4-[3-hydroxy-2-thienyl]-2-oxobut-3-enoate nor 2-mercaptophenylglyoxalate was detected. Cell extracts of strain RE204 catalyzed the conversion of cis-4,5-dihydroxy-4,5-dihydrobenzothiophene to trans-4-[3-hydroxy-2-thienyl]-2-oxobut-3-enoate in the presence of NAD+. Under the same conditions, extracts of the 3-isopropylcatechol-2,3-dioxygenase-deficient mutant RE215 acted on cis-4,5-dihydroxy-4,5-dihydrobenzothiophene, forming 4,5-dihydroxybenzothiophene. These data indicate that oxidation of benzothiophene by strain RE204 is initiated at either ring. Transformation initiated at the 4,5 position on the benzene ring proceeds by three enzyme-catalyzed reactions through ring cleavage. The sequence of events that occurs following attack at the 2,3 position of the thiophene ring is less clear, but it is proposed that 2,3 dioxygenation yields a product that is both a cis-dihydrodiol and a thiohemiacetal, which as a result of this structure undergoes two competing reactions: either spontaneous opening of the ring, yielding 2'-mercaptomandelaldehyde, or oxidation by the dihydrodiol dehydrogenase to another thiohemiacetal, 2-hydroxy-3-oxo-2,3-dihydrobenzothiophene, which is not a substrate for the ring cleavage dioxygenase but which spontaneously opens to form 2-mercaptophenylglyoxaldehyde and subsequently 2-mercaptophenylglyoxalate. The yellow product, trans-4-[3-hydroxy-2-thienyl]-2-oxobut-3-enoate, is a structural analog of trans-o-hydroxybenzylidenepyruvate, an intermediate of the naphthalene catabolic pathway; extracts of recombinant bacteria containing trans-o-hydroxybenzylidenepyruvate hydratase-aldolase catalyzed the conversion of trans-4-[3-hydroxy-2-thienyl]-2-oxobut-3-enoate to 3-hydroxythiophene-2-carboxaldehyde, which could then be further acted on, in the presence of NAD+, by extracts of recombinant bacteria containing the subsequent enzyme of the naphthalene pathway, salicylaldehyde dehydrogenase.     

Effect of substituents of the benzoquinone ring on electron-transfer activities of ubiquinone derivatives

The effect of substituents on the 1,4-benzoquinone ring of ubiquinone on its electron-transfer activity in the bovine heart mitochondrial succinate-cytochrome c reductase region is studied by using synthetic ubiquinone derivatives that have a decyl (or geranyl) side-chain at the 6-position and various arrangements of methyl, methoxy and hydrogen in the 2, 3 and 5 positions of the benzoquinone ring. The reduction of quinone derivatives by succinate is measured with succinate-ubiquinone reductase and with succinate-cytochrome c reductase. Oxidation of quinol derivatives is measured with ubiquinol-cytochrome c reductase. The electron-transfer efficacy of quinone derivatives is compared to that of 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone. When quinone derivatives are used as the electron acceptor for succinate-ubiquinone reductase, the methyl group at the 5-position is less important than are the methoxy groups at the 2- and 3-positions. Replacing the 5-methyl group with hydrogen causes a slight increase in activity. However, replacing one or both of 2- and 3-methoxy groups with a methyl completely abolishes electron-acceptor activity. Replacing the 3-methoxy group with hydrogen results in a complete loss of electron-acceptor activity, while replacing the 2-methoxy with hydrogen results in an activity decrease by 70%, suggesting that the methoxy group at the 3-position is more specific than that at the 2-position. The structural requirements for quinol derivatives to be oxidized by ubiquinol-cytochrome c reductase are less strict. All 1,4-benzoquinol derivatives examined show partial activity when used as electron donors for ubiquinol-cytochrome c reductase. Derivatives that possess one unsubstituted position at 2, 3 or 5, with a decyl group at the 6-position, show substrate inhibition at high concentrations. Such substrate inhibition is not observed when fully substituted derivatives are used. The structural requirements for quinone derivatives to be reduced by succinate-cytochrome c reductase are less specific than those for succinate-ubiquinone reductase. Replacing one or both of the 2- and 3-methoxy groups with a methyl and keeping the 5-position unsubstituted (plastoquinone derivatives) yields derivatives with no acceptor activity for succinate-Q reductase. However, these derivatives are reducible by succinate in the presence of succinate-cytochrome c reductase. This reduction is antimycin-sensitive and requires endogenous ubiquinone, suggesting that these (plastoquinone) derivatives can only accept electrons from the ubisemiquinone radical at the Qi site of ubiquinol-cytochrome c reductase, and cannot accept electrons from the QPs of succinate-ubiquinone reductase.     

Synthesis and evaluation of new arylbenzo[b]thiophene and diarylthiophene derivatives as inhibitors of the NorA multidrug transporter of Staphylococcus aureus

The synthesis based on palladium catalytic coupling of 38 new-arylated benzo[b]thiophenes or thiophenes is described in a few steps. We also report the direct arylation of the position 3 of the benzo[b]thiophenic structure, a 'one pot' 2,5-heterodiarylation of thiophenes as well as the synthesis of precursors of amino-acids with a 2-arylated benzo[b]thiophene core. These compounds were evaluated on bacteria strains: most of them did not exhibit any antibiotic activity but were found to selectively inhibit the NorA multidrug transporter of Staphylococcus aureus. As such, they restored the activity of the NorA substrates ciprofloxacin against a resistant S. aureus strain in which this efflux pump is over-expressed.     

The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4

A number of analogues of combretastatin A-4 (1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[b]thiophenes 3-5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than 1 but exhibit comparable activity to the most active of the benzo[b]thiophenes 3-5. A structure-activity relationship of these compounds is considered.     

N⁴-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation

With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).     

Synthesis of bicyclic biaryls as glucose-6-phosphatase inhibitors

Biaryls, 7-naphthyl-5-s-amino-2,3-dihydrobenzo[b]thiophene-4-carbonitriles (3a-e), 8-(1-naphthyl)-6-s-amino-isothiochroman-5-carbonitriles (6a-d), 4-(1-naphthyl)-2-s-aminobezocycloalkene-1-carbonitriles (6e-j), 8-naphthyl-6-s-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrle (6k-n), 1-naphthyl-3-s-amino-10H-9-thia-phenantherene-4-carbonitriles (8a-e) and 1-(1-naphthyl)-3-s-amino-9,10-dihydrophenantherene-4-carbonitriles (8f-i) have been prepared through carbanion induced ring transformation reactions of 6-naphthyl-3-cyano-4-s-amino-2H-pyran-2-ones (1) from respective ketones (2, 5, and 7). These compounds have been evaluated for their glucose-6-phosphatase inhibitory activity and only 6a, c, j, m, c, d, h displayed significant inhibition of the glucose-6-phosphatase.