Synthesis and Kinetic Evaluation of Inhibitors of the Phosphatidylinositol-Specific Phospholipase C from Bacillus cereus

Substrate analogues of phosphatidylinositol (1) were synthesized and evaluated as potential inhibitors of the bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus. The chiral analogues of the water-soluble phospholipid substrate 5 were designed to probe the effects of varying the inositol C-2 hydroxyl group, which is generally believed to serve as the nucleophile in the first step of the hydrolysis of phosphatidylinositols by PI-PLC. In the analogues 6-9, the C-2 hydroxyl group on the inositol ring of the phosphatidylinositol derivatives was rationally altered in several ways. Inversion of the stereochemistry at C-2 of the inositol ring led to the scyllo derivative 6. The inositol C-2 hydroxy group was replaced with inversion by a fluorine to produce the scyllo-fluoro inositol 7 and with a hydrogen atom to furnish the 2-deoxy compound 8. The C-2 hydroxyl group was O-methylated to prepare the methoxy derivative 9. The natural inositol configuration at C-2 was retained in the nonhydrolyzable phosphorodithioate analogue 10. The inhibition of PI-PLC by each of these analogues was then analyzed in a continuous assay using D-myo-inositol 1-(4-nitrophenyl phosphate) (25) as a chromogenic substrate. The kinetic parameters for each of these phosphatidylinositol derivatives were determined, and each was found to be a competitive inhibitor with K(i)'s as follows: 6, 0.2 mM; 10, 0.6 mM; 8, 2.6 mM; 9, 6.6 mM; and 7, 8.8 mM. This study further establishes that the hydrolysis of phosphatidylinositol analogues by bacterial PI-PLC requires not only the presence of a C-2 hydroxyl group on the inositol ring, but the stereochemistry at this position must also correspond to the natural myo-configuration. For future inhibitor design, it is perhaps noteworthy that the best inhibitors 6 and 10 each possess a hydroxyl group at the C-2 position. Several of the inhibitors identified in this study are now being used to obtain crystallographic information for an enzyme-inhibitor complex to gain further insights regarding the mechanism of hydrolysis of phosphatidylinositides by this PI-PLC.     

Synthesis, molecular structures, and chemistry of some new palladium(II) and platinum(II) complexes with pentafluorophenyl ligands

A series of palladium(II) and platinum(II) complexes possessing pentafluorophenyl ligands of the general formula [M(L-L)(C6F5)Cl][space](M = Pd 3; L-L=tmeda (N,N,N',N',-tetramethylethylenediamine) a; 1,2-bis(2,6-dimethylphenylimino)ethane) b; dmpe (1,2-bis(dimethylphosphino)ethane) c; dcpe (1,2-bis(dicyclohexylphosphino)ethane) d; Pt ; L-L=tmeda a; 1,2-bis[3,5-bis(trifluoromethyl)phenylimino]-1,2-dimethylethane b; dmpe c; dcpe d) were readily synthesized from the dimer [M(C6F5)(tht)(mu-Cl)2] (M=Pd 1b, Pt 2b; tht=tetrahydrothiophene) and the corresponding bidentate ligand. In the case of palladium, the corresponding iodo analogues (6a-c) were readily synthesized in a one-pot reaction from [Pd2(dba)3], iodopentafluorobenzene, and the appropriate ligand. The platinum complexes 4c-d were then converted to the water complexes [Pt(L-L)(C6F5)(OH2)]OTf (L-L =dmpe 7a; dcpe 7b)via reaction with AgOTf in the presence of water. Attempts to convert the palladium complexes 3c-d to the corresponding water complexes resulted in the disproportionation of the intermediate water complex to form [Pd(L-L)(C6F5)2] (L-L=dmpe 8) or [Pd(L-L)2][OTf]2(L-L=dcpe 9). Upon standing in solution for prolonged periods, complex 7a undergoes an identical disproportionation reaction to the Pd analogues to form [Pt(L-L)(C6F5)2] (L-L=dmpe 10). Complexes 4c and 4d were converted to the corresponding hydrides (11b-c, respectively) using two different hydride sources: 11a was formed by the reaction of with NaBH4 in refluxing THF, while 11b was synthesized in near quantitative yield using [Cp2ZrH2] in refluxing THF. Attempts to synthesize eta2-tetrafluorobenzyne complexes [Pt(L-L)(C6F4)] (L-L=dmpe, dcpe) from reaction of 11a-b with butyllithium were unsuccessful. The molecular structures of 3a,4a, 4c, 4d, 6b, 7a, 8, 11b and have been determined by X-ray crystallographic studies, and are discussed.     

Synthesis of perhydro-2(1H)-quinoxalinones and perhydropyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives

The novel trans-bicyclic-perhydro-2(1H)-quinoxalinones 4, 6 and 7 and the tricyclic-perhydropyrrolo[1,2-a]-quinoxalin-4(5H)-one derivatives 8 and 9 are prepared via a ring opening and spontaneous ring closing reaction of the aziridines 2 and 3 with the α-amino acids glycine, L-alanine, L-proline and L-phenylalanine. This methodology was used to prepare 5 and 10 which are novel rigid analogues of the kappa opioid compound 1. Treatment of aziridine 3 with methyl carbamate gave the cyclic urea 11.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo [4,3-b] pyridazine,III

s-Triazolo[4,3-b]pyridazine (I) reacted photochemieally with bieyélo[2.2.1] hepla-2,5-diene, 1,5-cyclooctadiene, 1,3-cyclooctadiene, methylene cyclohexane, diethyl cis-1,2,3,6-tetrahydro-phthalate and ethyl 2-cyclopentene-1-acetate to givt: the following products: the endo and exo isomers of 4a, 5, 8a, 9-tetrahydro-9-rnethylene-5,8-rnethano-8H-s-triuzolo[1, 5-a]indole (II) and the endo and exo-9-cyanometliyl products (III and IV) from bicyclo[2.2.1] hepta-2,5-diene; 4a,5,-9, 10, 10a, 11-huxahydro-11-methylene-6H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole (V) and the 11-cyanomethyl product VI from 1,5-cyclooctadiene: 4a,7,8,9,10,10a-hexahydro-11 -inethylene-11H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole(VII),4a, 5, 7, 8, 10a, 11-hexahydro-11-methylene-6H-cycloocta[4,5]pyrroIo[1,2-b]-s-triazole (VIII) and their respective 9-cyanomethyl products (X and 1X) from 1,3-cyclooctadiene; 6′, 7′ -dihydro-7′ -methylenespiro[cyclohexane-1, 5′-[5H] pyr-rolo[1,2-b]-s-triazole] (XI), 6′, 7′-dihydro-7′-meth) lene. spiro cyclohexane-1, 6′-[5H]pyrrolo[1,2-b]-s-triazole] (XII) and their respective 7 -eyanomethyl products (XIII and XIV) from melhylene cyclohexane; 6,7-dicarbethoxy-9-cyanomelhyl-4a, 5, 7, 8, 8a, 9-hexahydro-6H-s-triazolo[1,5-a]indole (XV) from diethyl cis-1, 2, 3, 6-tetrahydrophlhalate: and 5-earl)elhoxymethyl-8-eyanomethyl-4a, 5, 6, 7, 7a, 8-hexahydrocyclopenta[4,5]pyrrolo( 1, 2-b]-s-triazole (XVI) from ethyl 2, 2-cyclo-pentene-1-acetate. Many other alkenes, particularly the phenyl ethylenes, did not react with compound 1. In general, more than one product was isolated for each reaction except in the case of the two ester alkenes where a single eyanomethyl product was observed.     

New chemistry of 1,2-closo-P2B10H10 and 1,2-closo-As2B10H10; in silico and gas electron diffraction structures, and new metalladiphospha- and metalladiarsaboranes

The molecular structures of 1,2-closo-P(2)B(10)H(10) (1) and 1,2-closo-As(2)B(10)H(10) (2) have been determined by gas electron diffraction and the results obtained compared with those from computation at the MP2/6-31G** level of theory. The level of agreement is good for 2 (root-mean-square [rms] misfit for As and B atoms 0.0297 ?) and very good for 1 (rms misfit for P and B atoms 0.0082 ?). In comparing the structures of 1 and 2 with that of 1,2-closo-C(2)B(10)H(12) (I) it is evident that expansion of the polyhedron from I to 1 to 2 is restricted only to the heteroatom vertices and the B(6) face to which these are bound. Following deboronation (at B3) and subsequent metallation, compounds 1 and 2 have been converted into the new metalladiheteroboranes 3-(η-C(9)H(7))-3,1,2-closo-CoAs(2)B(9)H(9) (4), 3-(η-C(10)H(14))-3,1,2-closo-RuAs(2)B(9)H(9) (5), 3-(η-C(5)H(5))-3,1,2-closo-CoP(2)B(9)H(9) (6), 3-(η-C(9)H(7))-3,1,2-closo-CoP(2)B(9)H(9) (7) and 3-(η-C(10)H(14))-3,1,2-closo-RuP(2)B(9)H(9) (8), the last three constituting the first examples of metalladiphosphaboranes. Together with the known compound 3-(η-C(5)H(5))-3,1,2-closo-CoAs(2)B(9)H(9) (3), compounds 4-8 have been analysed by NMR spectroscopy and (except for 8) single-crystal X-ray diffraction. The (11)B NMR spectra of analogous pairs of metalladiphosphaborane and metalladiarsaborane (6 and 3, 7 and 4, 8 and 5) reveal a consistently narrower (9-10 ppm) chemical shift range for the metalladiarsaboranes, the combined result of a deshielding of the lowest frequency resonance (B6) and an increased shielding of the highest frequency resonance (B8) via an antipodal effect. In crystallographic studies, compounds 3 and 5B (one of two crystallographically-independent molecules) suffer As/B disorder, but in both cases it was possible to refine distinct, ordered, components of the disorder, the first time this has been reported for metalladiarsaboranes. Moreover, whilst the Cp compounds 6 and 3 are disordered, their indenyl analogues 7 and 4 are either ordered or significantly less disordered, a consequence of both the reduced symmetry of an indenyl ligand compared to a Cp ligand and the preference of the former for a distinct conformation relative to the cage heteroatoms. Unexpectedly, whilst this conformation in the cobaltadiphosphaborane 7 is cis-staggered (similar to that previously established for the analogous cobaltadicarborane), in the cobaltadiarsaborane 4 the conformation is close to cis-eclipsed.     

Synthesis and reactions of 11H‐benzo[b]pyrano[3,2‐f]indolizines an pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolines

2‐Methyl‐3H‐indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4‐hydroxy‐11H‐benzo[b]pyrano[3,2‐f]indolizin‐2,5‐diones 3, whereas 2‐mefhyl‐2,3‐dihydro‐1H‐indoles 9 give under similar conditions regioisomer 8‐hydroxy‐5‐methyl‐4,5‐dihydro‐pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolin‐7,10‐diones 10 . The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 or 5‐acetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo‐[3,2,1‐ij]quinolin‐4‐ones 11 , respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7‐dichloroacetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 5 or 5‐dichloracetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 12 . The dichloroacetyl group of 5 can be reduced with zinc to 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8‐hydroxy‐10H‐pyrido[1,2‐a]‐indol‐6‐ones 6 and 8 , and 6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 13 . Reaction of dichloroacetyl compounds 12 with sodium azide yields 6‐hydroxy‐2‐methyl‐5‐(1H‐tetrazol‐5‐ylcarbonyl)‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 14 via intermediate geminal diazides.     

A Direct Synthesis for a New Series of 2‐Oxo(thioxo)nicotinonitrile Nucleosides as Antimicrobial Agents

A facile synthesis of a new series of cyclic and acyclic nucleosides of polyfunctionalized 2‐oxo(thioxo)nicotinonitrile derivatives 1 and 2 was performed. Glycosylation of 2‐pyridone 1 and 2‐thiopyridone 2 with glycosyl/galactosyl bromides in the existence of KOH afforded the N‐nucleoside and S‐nucleoside analogues 3 , 5 , 7 , and 9 , respectively. Deacetylation of nucleosides 3 , 5 , 7 , and 9 gave the deacetylated nucleosides 4 , 6 , 8 , and 10 , respectively. Alkylation of 2‐pyridone 1 with glycone analogues [namely, 4‐bromobutyl acetate, (2‐acetoxyethoxy)methyl bromide, 3‐chloropropane‐1,2‐diol, and allyl and / propargyl bromides] in the existence of K₂CO₃ afforded the corresponding O‐acyclic nucleoside analogues 11 , 13 , and 15–17 , respectively. Finally, treating of compounds 11 and 13 with a small amount of Et₃N tolerated the 6‐hydroxy deacetylated derivatives 12 and 14 , respectively. The synthesized nucleosides and alkylated products were tested against Gram (+ve) (Staphylococcus aureus and Bacillus cereus) and (Pseudomonas aeruginosa and Escherichia coli) as Gram (?ve) and Fungi (Aspergillus flavus and Aspergillus niger) and showed moderate antibacterial and antifungal activity.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

Inhibition of Glycosidases by Lactam Oximes: Influence of the Aglycon in Disaccharide Analogues

The influence of a substituent at the hydroximo function of the lactam analogue 1 on the inhibition of β- and α-glucosidases is evaluated. In contrast to 1 , the O-alkyl oximes 5 , 6 , 9 , and 10 are selective inhibitors of β-glucosidases. Alkylation of the D -gluconohydroximo-1,5-lactam 19 with the triflate 12 , or condensation of the thiogluconolactam 20 with the hydroxylamines 14 or 18 afforded the benzylated cellobioside analogues 21 and 23 , respectively. The O-alkyl oximes 33 and 39 were prepared similarly (Scheme 3). Deprotection afforded the cellobioside analogues 5 and 6 , and the O-alkyl oximes 9 and 10 . The lactam O-alkyl oximes 5 , 6 , 9 , and 10 are strong inhibitors of the β-glucosidase from C. saccharolyticum (IC₅₀=0.3 – 8 μM ) and, with exception of the dodecyl analogue 9 (IC₅₀=2 μM ), moderate-to-weak inhibitors of β-glucosidases from sweet almond (IC₅₀=60 – 1000 μM ; see Table). In contrast to the strong inhibition of α-glucosidase from brewer's yeast by 1 (K_i=2.9 μM ), the ethers 5 , 6 , and 10 are weak inhibitors of this enzyme (IC₅₀ between 2500 and >5000 μM ). Similarly, the D -galactohydroximo-1,5-lactam 7 is a potent inhibitor of the α-galactosidase from coffee beans and of the β-galactosidases from bovine liver and E. coli (K_i=5, 10, and 0.1 μM , resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β-galactosidase (K_i=0.1 μM ), but a moderate-to-weak inhibitor of coffee-bean α-galactosidase and bovine-liver β-galactosidase (K_i=250 μM and IC₅₀=2500 μM , resp.). The galacto-configured lactam oximes 7 and 8 are good inhibitors of the β-glucosidase isolated from C. saccharolyticum (K_i=2.5 and 3.3 μM , resp.).     

Synthesis and reactions of 10,10‐dimethyl‐10H‐pyrido[1,2‐a]indol‐6‐ones

Cyclocondensation of 2,3,3‐trimefhyl‐3H‐indoles 2 with malonates 3 gives 8‐hydroxy‐10,10‐dimefhyl‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 , which were halogenated in position 7, 8 and 9 with sulfuryl chloride, bromine or phosphoroxychloride to give the corresponding halo‐10,10‐dimethyl‐10H‐pyrido[1,2‐a]indoles 5, 6, 7 and 8 . Amination affords the 8‐amino‐10,10‐dimethyl‐10H‐pyrido[1,2‐a]indol‐6‐one 9 . Nitration gives either the 10,10‐dimethyl‐7‐nitro‐10H‐pyrido[1,2‐a]indoles 10 or 10,10‐dimethyl‐7‐hydroxy‐10H‐pyrido[1,2‐a]indoles 11 , depending on the conditions.     

Synthesis of 1-arylacenaphtho[1,2-d]pyrazoles and 5,7-Dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes

2-Benzoyl- 5 and 2-acetylacenaphthenone 6 , prepared from the corresponding 1-acyl-2-(1-pyrrolidinyl)-acenaphthylenes 2 and 3 , reacted with arylhydrazines 8 under acidic conditions to give the corresponding 1-arylacenaphtho[1,2-d]pyrazoles 9 and 10 . Novel heteropentalene mesomeric betaines, 5,7-dehydro-5H,7H-benzo[b]acenaphtho[1,2-e]-1,3a,6a-triazapentalenes 13 and 14 were prepared by reductive cyclization of 1-(o-nitrophenyl)acenaphtho[1,2-d]pyrazoles 9d and 10d , respectively.     

Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza-naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring transformation of suitably functionalized 2H-pyran-2-one with α-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles) followed by their photocyclization either in CHCl₃ or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.     

Preparation of cis-5-methoxy-and-7-methoxy-1-acetoxy-1,2,3,4,4a,10a- hexahydro-9(10H)-phenanthrenone. An epoxide-arene reaction involving a selective 1,2-alkyl shift rearrangement.

The preparation of cis-1-acetoxy-7-methoxy-1,2,3,4,4a,10a-hexahydro-9(10H)- phenanthrenone 5 was accomplished starting from 6-methoxy-1-tetralone. Reduction of 7-methoxy-1,2,3, 4,9,10-hexahydro-1-oxo-phenanthrene 8, acetylation and subsequent oxidation delivered 5. Application of an analogus procedure to the preparation of cis-1β-acetoxy-5-methoxy-1,2,3,4,,4a,10a-hexahydro-9(10H)- phenanthrenone 6 was not feasible. A more elaborate route was developed for the synthesis of compound 6, where an epoxide-arene reaction involving a 1,2-alkyl shift rearrangement, constituted a highly selective key transformation.     

Reactions of Diferrocenylmorpholino- and -Methylsulfanyl-cyclopropenylium Salts with β-Dicarbonyl Compounds and Diethyl Malonate

2,3-Diferrocenyl-1-morpholinocyclopropenylium tetrafluoroborate reacts with ethyl acetoacetate, ethyl benzoylacetate, and diethyl malonate in the presence of triethylamine to yield 3-[acyl(ethoxycarbonyl)]-, 3-(diethoxycarbonyl)-methyl-3-morpholino-1,2-diferrocenylcyclopropenes (3a–c), and 3-[acyl(ethoxycarbonyl)]- and (diethoxycarbonyl)-methylidene-1,2-diferrocenylcyclopropenes (4a–c) in a ca. 1:1.5 ratio. 2,3-Diferrocenyl-1-methylsulfanylcyclopropenylium iodide with the same substrates affords compounds 4a,b (～10–15%), 3-[acyl(ethoxycarbonyl)]methyl-3-methylsulfanyl-1,2-diferrocenylcyclopropenes (5a,b) (～8–10%), 2-acyl-3,4-diferrocenyl-5-methylsulfanylcyclopentadienones (6a,b), ethyl 2-acyl-3,4-diferrocenyl-5-methylsulfanylpenta-2,4-dienoates (7a,b; 8a,b), and ethyl 3,4-diferrocenyl-2-methylsulfanyl-6-oxohexa(hepta)-2,4-dienoates (9a,b). The spatial structure of ethyl Z,E-3,4-diferrocenyl-2-methylsulfanyl-6-oxohepta-2,4-dienoate (9b) was established based on the data from x-ray diffraction analysis. Electrochemical properties of 3-[acyl(ethoxycarbonyl)]- and (diethoxycarbonyl)-methylidene-1,2-diferrocenylcyclopropenes (4a–c) are studied.     

Crystallography,Molecular Modeling,and COX-2 Inhibition Studies on Indolizine Derivatives

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC₅₀ of 5.84 µM, as compared to indomethacin (IC₅₀ = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 2₁/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)ų. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.     

Recognition of Artificial Nucleobases by E. coli Purine Nucleoside Phosphorylase versus its Ser90Ala Mutant in the Synthesis of Base‐Modified Nucleosides

A wide range of natural purine analogues was used as probe to assess the mechanism of recognition by the wild‐type (WT) E. coli purine nucleoside phosphorylase (PNP) versus its Ser90Ala mutant. The results were analyzed from viewpoint of the role of the Ser90 residue and the structural features of the bases. It was found that the Ser90 residue of the PNP 1) plays an important role in the binding and activation of 8‐aza‐7‐deazapurines in the synthesis of their nucleosides, 2) participates in the binding of α‐D ‐pentofuranose‐1‐phosphates at the catalytic site of the PNP, and 3) catalyzes the dephosphorylation of intermediary formed 2‐deoxy‐α‐D ‐ribofuranose‐1‐phosphate in the trans‐2‐deoxyribosylation reaction. 5‐Aza‐7‐deazaguanine manifested excellent substrate activity for both enzymes, 8‐amino‐7‐thiaguanine and 2‐aminobenzothiazole showed no substrate activity for both enzymes. On the contrary, the 2‐amino derivatives of benzimidazole and benzoxazole are substrates and are converted into the N1‐ and unusual N2‐glycosides, respectively. 9‐Deaza‐5‐iodoxanthine showed moderate inhibitory activity of the WT E. coli PNP, whereas 9‐deazaxanthine and its 2′‐deoxyriboside are weak inhibitors.     

Stereoselective Synthesis of 5a-Ethyl-1,2,3,3a,4,5,5a,6,9a,9b-decahydro- 1,3,4-trihydroxy-3a-(hydroxymethyl)-7H-benz[e]inden-7-one Derivatives

Homochiral Diels-Alder cyclodimerization of (±)-6-ethenyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-ol ( 1 ) followed by oxidation gives (1RS,4RS,4aSR,4bSR,5RS,8RS,8aRS)-8a-ethenyl-1,3,4,4a,4b,5,6,8,8a,9-decahydro-1,4:5,8-diepoxyphenanthrene-2,7-dione ( 18 ). Selective hydrogenation followed by epoxidation produced (1RS,4RS,4aRS,5aRS,6aRS,7RS,10RS,10aSR,10bRS)-6a-ethyl-1,4,5a,6,6a,7,9,10,10a,10b-decahydro-1,4:7,10-diepoxyphenanthro[8a,9-b]oxirene-3,8-dione ( 21 ), which was solvolyzed (Me₃SiOSO₂CF₃, Piv₂O) with concomitant pinacol rearrangement involving an acyl-group migration to give a 6-oxo-7-oxabicyclo[2.2.1]hept-2-yl cation intermediate, which finally generated (1RS,3SR,3aRS,4SR,5aRS,6RS,9RS,9aSR,9bSR)-5a-ethyl-1,4,5,5a,6,7,8,9,9a,9b-decahydro-7,10-dioxo-3H-6,9-epoxy-1,3a-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 24 ). Photo-reductive 7-oxa bridge opening of 24 , followed by water elimination and silylation, provided (1RS,3SR,3aRS,4SR,5aSR,9aSR,9bSR)-7-{[(tert-butyl)dimethylsilyl]oxy}-5a-ethyl-1,4,5,5a,9a,9b-hexahydro-10-oxo-3H-1,3-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 34 ). Reduction of 34 with NaBH₄ in MeOH followed by desilylation and alcohol protection produced (1RS,3RS,3aRS,4SR,5aSR,9aSR,9bSR)-5a-ethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-1,3-bis(methoxymethoxy)-3a-[(methoxymethoxy)methyl]-7-oxo-1H-benz[e]inden-4-yl 2,2-dimethylpropanoate ( 5 ), a polyoxy-substituted decahydro-1H-benz[e]indene derivative with cis-transoid-trans junction for the two cyclohexane and the cyclopentane rings bearing an angular 3a-(oxymethyl) substituent.     

Benzolactams. 4. Reaction of 3',4'- or 4',5'-dialkoxy-substituted 1-(2'-Bromobenzyl)-2-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinolines with alkyllithium. 1,2 and 1,4 additions of alkyllithium to benzolactams

Treatment of 1-(2'-bromo-3',4'-dialkoxybenzyl)-1,2,3, 4-tetrahydroisoquinoline carbamates, 1a,c, with excess alkyllithium gave 8-oxoberbines, 2a,c, which were successively attacked in situ with another molecule of alkyllithium to give 1,2 and/or 1,4 addition products. A primary alkyllithium, such as MeLi or BuLi, gave a 1,2 addition product, 8-methyleneberbine 9a or 8-butylideneberbine 3a. t-BuLi preferred 1,4 addition, followed by elimination of the alkoxy group, to give 9-tert-butyl-8-oxoberbine 6a or 7c. s-BuLi gave a mixture of 1,2 and 1,4 addition products, 1-[2'-(2' '-methylbutyryl)benzyl]-1,2,3,4-tetrahydroisoquinoline 4a and 9-s-butyl-8-oxoberbine 5a. Similar treatments of carbamate 1b having no alkoxy group at its 3' position gave 1,2 addition products, 8-butylideneberbine 3b, 1-[2'-(2' '-methylbutyryl)benzyl]-1,2,3, 4-tetrahydroisoquinoline 4b, and 1-(2'-pivaloylbenzyl)-1,2,3, 4-tetrahydroisoquinoline 6b, in all cases. Reactions of 1a with s-BuMgCl and isoPrMgCl also gave the 1,4 adduct, 5a, and its 9-isoPr analogue, 12a. Treatment of 9a with excess NaBH(4) in AcOH gave (+/-)-coralydine (10b).     

Synthesis of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoyl-1,2-dihydropyridines and their cyclization to 5-phenyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones

The regiospecific reaction of 3-benzyloxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6a) , or 3-t-butoxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6b) , with either acetyl chloride or ethyl chloroformate, and either n-butylmagnesium chloride or phenylmagnesium bromide afforded the respective 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-benzyloxy (or t-butoxy) carbonylaminomethylcarbonylami-no-4-benzoyl-1,2-dihydropyridines 7 in 60-75% yield. Reaction of 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-t-butoxycarbonylaminomethylcarbonyl-4-benzoyl-1,2-dihydropyridines 7b, 7f, 7d, 7h with trifluoroacetic acid gave the corresponding 5-phenyl-8-acetyl (or ethoxycarbonyl)-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b, 8c, 8d respectively in 45–63% yield. N¹-Methylation of 5-phenyl-8-acetyl-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b using sodium hydride and iodomethane yielded the corresponding N¹-methyl derivatives 9a (48%) and 9b (54%). Oxidation of 5,9-diphenyl-8-ethoxycarbonyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8d) using p-chloranil afforded 1,3-dihydro-5,9-diphenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one (10) . 5-Phenyl-8-acetyl-9-n-butyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8a) and the corresponding 8-ethoxycarbonyl analog 8c exhibited weak anticonvulsant activity indicating that 8a and 8c may be acting at the same site as the 7-halo-1,4-benzodiazepin-2-one class of compounds.     

Stereoselective inhibition of alpha-L-fucosidases by N-benzyl aminocyclopentitols

[structure: see text] (1R,2R,3R,4R,5R)-4-Amino-5-methylcyclopentane-1,2,3 -tr iol 8, its 4S stereoisomer 9, and their acyclic analogues (R)- and (S)-2-aminobutanol 11 and 12 are selective but moderate inhibitors of alpha-L-fucosidases. N-Benzylation selectively enhances inhibition potency for aminocyclopentitol 8 (--> 1, K(i) = 6.8 x 10(-)(7) M) but decreases inhibition for its 4S-stereoisomer 9 (--> 2, K(i) = 1.1 x 10(-)(4) M) and for the aminobutanols 11 (--> 13, no inhibition) and 12 (--> 14, no inhibition).