Analogues 1a Research Articles

Synthesis of (Z)-(2,3-bis-Hydroxymethyl)methylenecyclopropane Analogues of Purine Nucleosides

Synthesis of (Z)-(2,3-bis-hydroxymethyl)methylenecyclopropane analogues of nucleosides adenosine 10a, 10b, 10c and 17 is described. Epimerization of Feist's acid (11) using acetic anhydride gave cyclic anhydride 12 which was reduced in situ to give diol 13. Acetylation (compound 14) followed by addition of bromine led to dibromo derivative 15. Alkylation-elimination of adenine with 15 afforded, after deacetylation, analogue 10a. Similar treatment of 2-amino-6-chloropurine and 2,6-diaminopurine led to diacetates 16 and 18. Deprotection then gave compounds 17 and 10c. Hydrolysis of 17 furnished guanine analogue 10b. Compounds 10a, 10b or 10c were inactive against HCMV, HSV-1, HSV-2, EBV, VZV and HBV. Analogues 10a and 10b were also assayed for anti-HIV activity. Compound 10a was effective in HIV-1/MT-2 culture with EC50/CC50 33/> 100 µM but 10b was inactive. Analogue 10a was not a substrate for adenosine deaminase.

Synthesis of 5- endo-, 5- exo-, 6- endo- and 6- exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one ( 7 ) was developed by SmI 2-mediated desulfonylation of 6 . Thus, 5- endo-, 5- exo-, 6- endo-, and 6- exo-hydroxylated epibatidine analogues 2a, b and 3a, b were synthesized from 7 by using a Pd(PPh 3) 4-catalyzed reductive Heck coupling reaction and SmI 2-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.

Design and Efficient Synthesis of New Stable 1α,25‐Dihydroxy‐19‐norvitamin D3 Analogues Containing Amide Bond.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Structure-activity relationships of (S,Z)-2-aminopurine methylenecyclopropane analogues of nucleosides. Variation of purine-6 substituents and activity against herpesviruses and hepatitis B virus.

A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N(6)-alkyl compounds 2a, 2b, 2c, 2d, 2e,2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K(2)CO(3) afforded O(6)-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S(6)-alkyl compounds 4h and 4i. The N(6)-alkyl derivatives 2a, 2b, O(6) analogues 3a, 3c, 3h, 3i, and S(6) compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.

An Approach to Novel Fused Triazole or Tetrazole Derivatives Starting from Benzimidazo[1,2‐a]quinazoline‐5(7H)‐one and 5,7‐Dihydro‐5‐oxopyrido[3′,2′:5,6]pyrimido[1,2‐a]benzimidazole.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A highly efficient olefin metathesis initiator: improved synthesis and reactivity studies

The synthesis of ligand 8 , required for the preparation of catalyst 4c has been optimised. Ligand exchange studies indicate that biphenyl-based alkylidene 4c initiates considerably faster than its unsubstituted analogue 4a . The performance of 4c in ring-opening cross metathesis reactions involving substrates containing unprotected chelating atoms is also reported.

Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation.

We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha production with an ED50 value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-alpha production in vivo as well as oral bioavailability.

Solid-phase synthesis of amine-bridged cyclic enkephalin analogues via on-resin cyclization utilizing the Fukuyama-Mitsunobu reaction.

An efficient solid-phase synthetic route is described for the preparation of 13-membered amine-bridged cyclic enkephalin analogues (ABEs) 1a and 1c-1j (Figure 1) resulting from a sulfonamide-containing peptide whose backbone is bound to a resin. The Fukuyama-Mitsunobu reaction of the 2-nitrobenzenesulfonyl-protected amine bound to the solid support with protected aminoethanol in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) is utilized to prepare a resin-bound sulfonamide-protected secondary amine. After peptide cyclization, this protected amine functionality becomes the "amine bridge" of the target molecule. In addition, the reagent DIAD was found to be a superior reagent compared to diethyl azodicarboxylate (DEAD) in the solid-phase Fukuyama-Mitsunobu reaction.

Design and efficient synthesis of new stable 1α,25-dihydroxy-19-norvitamin D 3 analogues containing amide bond

The design and synthesis of new 1α,25-dihydroxy-19-norvitamin D 3 analogues 3a– c, which have an amide bond in the molecule instead of the diene, are described. The A-ring moiety was constructed by a (3 S,5 S)-3,5-dihydroxypiperidine derivative ( 9, 11, or 13) prepared from d-mannose, and a CD-ring carboxylic acid 16 was synthesized from Grundmann's ketone. Coupling those parts gave desired 3a– c in good yield. This strategy can be applied in combinatorial chemistry; therefore, those compounds would be applicable as useful tools in the development of new drugs.

Synthesis and Affinity Studies of Himbacine Derived Muscarinic Receptor Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An approach to novel fused triazole or tetrazole derivatives starting from benzimidazo[1,2‐a]quinazoline‐5(7H)‐one and 5,7‐dihydro‐5‐oxopyrido[3′,2′:5,6]pyrimido[1,2‐a]benzimidazole

AbstractThe synthetic potential of the title compounds benzimidazo[1,2‐a]quinazoline‐5(7H)‐one 2a and 5,7‐dihydro‐5‐oxopyrido[3′,2′:5,6]pyrimido[1,2‐a]benzimidazole 2b for the construction of novel polyhetero‐cyclic frameworks is reported. Compounds 2a,b, by conversion into their thio analogues 3a,b, were used for the synthesis of tetrazole (5a,b) and triazole (7a,b) derivatives, as well as for an unexpected synthesis of tri‐azoles 8a,b, isomers of 7a,b, resulting from the occurrence of a Dimroth rearrangement.

2-Methylimidazol-1-yl-Substituted Analogs of Hexahydro-difenidol (HHD) and Hexahydro-sila-difenidol (HHSiD) as M3 Receptor-Preferring Muscarinic Antagonists: A Study on C/Si Bioisosterism

The hexahydro-sila-difenidol (HHSiD, 1b) and p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD, 2b) derivatives cyclohexyl[3-(2-methylimidazol-1-yl)propyl]phenylsilanol (4b) and cyclohexyl(4-fluorophenyl)[3-(2-methylimidazol-1-yl)propyl]silanol (5b) were synthesized in three-step syntheses, starting from (3-chloropropyl)cyclohexyldimethoxysilane. In addition, the corresponding carbon analogs 4a and 5a (→ Si/C replacement) were prepared in two-step syntheses, starting from 2-(3-chloropropyl)-2-phenyl-1,3-dioxolane and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane, respectively. The C/Si pairs 4a/4b and 5a/5b were studied for their affinities at recombinant human muscarinic M1, M2, M3, M4, and M5 receptors stably expressed in CHO-K1 cells by evaluating their ability to inhibit the binding of the muscarinic antagonist [3H]N-methylscopolamine. These studies revealed that compounds 4a, 4b, 5a, and 5b behave as simple competitive antagonists at M1−M5 receptors. The exchange of the piperidin-1-yl group of the parent compounds HHD (1a), HHSiD (1b), p-F-HHD (2a), and p-F-HHSiD (2b) by a 2-methylimidazol-1-yl moiety resulted in a novel, potent, and M3-preferring antimuscarinic agent, compound 4b. The affinities of compounds 4a, 5a, and 5b for muscarinic M1 (pKi = 7.74−7.93), M2 (pKi = 7.03−7.14), M3 (pKi = 8.04−8.11), M4 (pKi = 7.63−7.94), and M5 receptors (pKi = 7.29−7.52) were very similar at the individual receptor subtypes and in turn very similar to those of the parent compounds 1a, 2a, and 2b. In contrast, replacement of the piperidin-1-yl substituent of 1b by a 2-methylimidazol-1-yl group (→ 4b) increased the affinity for M1−M5 receptors up to 8.3-fold. The muscarinic receptor affinity profile of 4b was found to be M3 (pKi = 8.69) > M1 (pKi = 8.39) ≥ M4 (pKi = 8.32) > M5 (pKi = 8.02) > M2 (pKi = 7.43). Thus, compound 4b displayed a M3 versus M2 receptor selectivity (18.2-fold). The receptor subtype affinities of the carbon compound 5a were very similar to those of the corresponding silicon analog 5b, whereas sila-substitution of 4a (→ 4b) increased the affinities for M1−M5 receptors, this increase being greatest at M3 and M5 receptors (4-fold).

Metathesis of Olefin-Substituted Pyridines: The Metalated NCN-Pincer Complex in a Dual Role as Protecting Group and Scaffold Part of this work was presented at the 14th International Symposium on Olefin Metathesis, Boston, August 2001

Pincer-palladium(II) and -platinum(II) cat- ions, YCY-M (YCY (2,6-(YCH2)2C6H3) ;Y NMe2, SPh; M Pd II ,P t II ), bound to diolefin-substituted pyridines (3,5- or 2,6-substitution) were successfully synthesized, and subsequently used in olefin meta- thesis (RCM) as a model study for template-directed synthesis of macrocycles. Especially a 3,5-disubstitut- ed pyridine bound to a NCN-Pt II -center (5a) gave a fast metathesis reaction, while the same reaction with the Pd II analogue (4a) was much slower and less selective (isomerization products were formed). Fur- thermore, it was found that 2,6-diolefin-substituted pyridines (4b, 5b, 5c) gave slow metathesis reactions, which is mainly ascribed tosteric hindrance during the ring-closing step. In all cases where prolonged reaction times were required an isomerization pro- cess, most likely assisted by cationic pincer-M II species, was observed as a competing reaction. 1 HN MR spectroscopy experiments revealed that pyridines are stronger bound to a cationic NCN-Pt II -center than toits Pd II -analogue. This aspect is of crucial importance when these pincer-pyridine complexes are applied in metathesis, since free pyridine in solution deactivates the Ru-metathesis catalyst. For the tem- plated construction of macrocycles, a strong M-N(py) bond is also important since it determines the selectivity for the desired product. In addition, these results open a new research field in which organo- metallic (pincer) complexes are used as protecting groups for strong Lewis-basic groups in catalysis. From failed attempts to prepare macrocycles using hexakis(SCS-Pd II -(1a)) complex 14, and from the results obtained with the monometallic pincer com- plexes in RCM, it can be concluded that the most suitable candidate for constructing macrocycles should comprise 2,6-diolefin-substituted pyridines bound to a multi-(NCN-Pt II )-template. In such a system, intrapyridine metathesis (steric hindrance) as well as isomerization reactions (strong M-N(py) bond) are suppressed.

Structure–activity relationship study at the 3′- N-position of paclitaxel: synthesis and biological evaluation of 3′- N-acyl-paclitaxel analogues

A series of 3′- N-acyl-paclitaxel analogues 1a– v were synthesized and their cytotoxicities in vitro against several human tumor cell lines examined. It has been shown that distinct correlation between activity and N-acyl-substituent. The appropriate size of N-acyl group was indispensable for cytotoxicity, and moreover, the presence of β-substituted conjugated double and triple bond to N-carbonyl generally resulted in increase of cytotoxicities.

Synthesis and affinity studies of himbacine derived muscarinic receptor antagonists

A series of himbacine ( 1)-related analogues has been prepared featuring three different isomeric configurations with respect to the B-ring ( a, b and natural c) and three different interconnecting two-carbon unsaturated units [natural ( E)-ene, ( Z)-ene, and yne]. The study of the binding affinities of the nine resulting compounds, including synthetic (+)-himbacine ( 3c), towards the M 1–M 4 muscarine receptor subtypes revealed that analogues 3a and 5c display a promising 10-fold selectivity for the M 2 receptor as compared to the M 1 receptor.

Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands.

The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[D-Ala(L)-Gly-Phe-D-Ala(L)]-OH (1a), Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (1b), Tyr-c[D-Ala(L)-Gly-Phe-Ala(L)]-OH (1c), and Tyr-c[D-Val(L)-Gly-Phe-Ala(L)]-OH (1d), where Ala(L) and Val(L) denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against mu-, delta-, and kappa-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as D-Val(L) in position 2, show substantial selectivity toward the delta-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as D-Ala(L) in position 2, bind to both mu- and delta-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the delta-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that mu- and delta-opioid receptors interact synergistically to modulate the antinociceptive responses.

Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.

A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.

Influence of Chain Length on the Electrophilic Reactivity of Carbocations

The electrophilic reactivities of the bis(p-methylphenyl)carbenium ion 1b+ and its macromolecular analogue 1a+ have been compared in slow reactions with allylsilanes and in fast reactions with sily...

Carbanions as Intermediates in the Formation of Grignard Reagents

The reaction between certain aryl bromides RBr having substituents with group 14 elements and magnesium in THF to form the corresponding Grignard reagents RMgBr were found to be accompanied by unusual migrations of the group 14 functionality; it partially exchanges position with that of the original aryl bromide function. This migration is purely intramolecular for organosilicon derivatives but both intra- and intermolecular for the corresponding tin compounds. For example, 1-bromo-2-((trimethylsilyl)methyl)benzene (1b) gives rise to 1-(bromomagnesio)-2-((trimethylsilyl)methyl)benzene (2b) and to its intramolecular rearrangement product 1-((bromomagnesio)methyl)-2-(trimethylsilyl)benzene (3b), whereas the trimethylstannyl analogue 1a forms, in addition to the two corresponding Grignard reagents 2a and 3a formed by the intramolecular pathway, the intermolecular exchange products 1-(trimethylstannyl)-2-((trimethylstannyl)methyl)benzene (4a) and 1-(bromomagnesio)-2-((bromomagnesio)methyl)benzene (5‘). These ...

2,2-Disubstituted analogues of the natural hormone 1α,25-dihydroxyvitamin D3: chemistry and biology

Six new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels–Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues 8. Analogues 7a and 8a are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2–3 times more active transcriptionally than calcitriol, whereas dimethylated analogue 8a is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue 8a is considerably less calcemic than calcitriol. Dimethylated analogue 8a strongly suppresses parathyroid hormone (PTH) secretion.