Studies on the synthesis of compounds related to adenosine 3',5'-cyclic phosphate. VII. Synthesis and cardiac effects of N6,N6-dialkyl adenosine 3',5'-cyclic phosphates

A series of novel N6,N6-dialkyl adenosine 3',5'-cyclic phosphates N6,N6-dialkyl cAMPs) was synthesized from 2'-O-p-toluenesulfonyl cAMP (2'-O-tosyl cAMP, 2) and tested for inotropic and chronotropic activities in vitro. Treatment of 2 with excess alkyl halides and sodium hydride followed by detosylation with aqueous NaOH readily gave N6,N6-dialkyl cAMPs (3) in good yields. Various N6,N6-dialkyl cAMPs having different alkyl groups at the N6-position (9-12) were prepared by alkylation followed by detosylation of N6-alkyl-2'-O-tosyl cAMPs (4) which were obtained by the reductive alkylation of 2 with aldehydes in the presence of sodium cyanoborohydride in acetic acid or tosylation of N6-methyl cAMP. The mechanism of the detosylation is briefly discussed. Among the N6,N6-dialkylated derivatives, N6,N6-dipentyl (3f) and N6-ethyl-N6-heptyl (10e) derivatives were found to exhibit a potent positive inotropic effect and a weak positive chronotropic effect. The structure-activity relationships for the position and the length of alkyl residue are discussed.     

Studies on the synthesis of compounds related to adenosine 3',5'-cyclic phosphate. IX. Synthesis and cytotoxic effect of adenosine 3',5'-cyclic alkylphosphoramidates.

A series of adenosine 3',5'-cyclic monophosphoramidates (3, cAMP amidates), including long-chain alkyl amidates, were synthesized from adenosine 3',5'-cyclic monophosphate (1, cAMP) by means of a one-pot reaction. This reaction proceeded by the treatment of cAMP tributylammonium salt (2) with phosphorus pentachloride (PCl5) and alkylamine in N,N-dimethylformamide (DMF). Compounds 3 synthesized were investigated to determine their cytotoxic activities on the growth of mouse mastocytoma P-815 cells, mouse mammary tumor FM3A cells, and human mammary tumor ZR-75 cells in culture. It was found that compounds 3h-m showed significant cytotoxic activities against these cell lines, and that cAMP decylamidate (3j) was the most cytotoxic compound (the concentration required for 50% inhibition of cell growth, ID50 = 6.0, 15.0, 2.2 microM, respectively); the antitumor effect on P-815 cells by a total packed cell volume method showed 81.8% inhibition. The cytotoxic activity of 3 increased with the increase in alkyl chain length up to 10 carbon atoms and decreased in compounds having longer alkyl chain.     

Novel 3',5'-cyclic nucleotide analogue: adenosine 3',5'-cyclic boranomonophosphate

A general procedure for the first synthesis of a 3',5'-cyclic boranomonophosphate was established. Specifically, adenosine 3',5'-cyclic boranomonophosphosphate (cyclic AMPB, 4c), a P-borane (BH(3)) analogue of adenosine 3',5'-cyclic monophosphate (cAMP), was synthesized via a phosphite approach in good yield. The method is also applicable for syntheses of natural cAMP and its phosphorothioate analogue. The two diasteromers of cyclic AMPB 4c were separated, and their chemical structures were established via spectroscopic methods.     

Synthesis and central nervous system depressant effects of N3-substituted 2',3'-O-isopropylideneuridines

N3-Substituted derivatives of 2',3'-O-isopropylideneuridine (1) were synthesized and their pharmacological effects on the central nervous system (CNS) examined using mice. Methyl (2), ethyl (3), propyl (4), butyl (5), allyl (6), benzyl (7), o-, m-, p-xylyls (8, 9, 10), and alpha-phenylethyl (11) derivatives of 1 were administered to mice by intracerebroventricular (i.c.v.) injection for evaluating hypnotic activity, pentobarbital-induced sleep prolongation, and spontaneous activity as indices. Only 3 possessed hypnotic activity by i.c.v. injection at the dose of 2.0 mumol/mouse. Compounds 3, 4, and 10 significantly showed synergism with a barbiturate, indicating that the derivatives have some CNS depressant effects. Moreover, 3 and 4 caused decrease in the spontaneous activity of mice, even at low doses. The present study indicated that substitution by ethyl, propyl, and p-xylyl groups at the N3-position of 2',3'-O-isopropylideneuridine imparted the CNS depressant effects.     

Condensation of thiourea with uracyl derivatives containing ketone and ketoester fragments,alkylation and macrocyclization of the condensation products

By condensation of thiourea with 6-methyluracyl derivatives containing ketone and ketoester fragmenst in the alkyl chains attached to the nitrogen atoms of the pyrimidine ring the products containing 6-methyl- or 3,6-dimethyluracyl fragment and one or two 6-methyl-4-oxo-2-thio-1,2,3,4-tetrahydropyrimidin-5-yl fragments were synthesized. These compounds can be alkylated with alkyl bromides.     

Deactivation behavior and excited-state properties of (coumarin-4-yl)methyl derivatives. 2. Photocleavage of selected (coumarin-4-yl)methyl-caged adenosine cyclic 3',5'-monophosphates with fluorescence enhancement

A series of axial and equatorial diastereomers of (coumarin-4-yl)methyl-caged adenosine cyclic 3',5'-monophosphates (cAMPs), 1-6, having methoxy, dialkylamino, or no substituent in the 6- and/or 7-positions, and their corresponding 4-(hydroxymethyl)coumarin photoproducts 7-12 have been synthesized. The photochemical and UV/vis spectroscopical properties (absorption and fluorescence) of 1-6 and 7-12 have been examined in methanol/aqueous HEPES buffer solution. Donor substitution in the 6-position causes a strong bathochromic shift of the long-wavelength absorption band, whereas substitution in the 7-position leads only to a weak red shift. The photochemical cleavage of the caged cAMPs was investigated, and the photoproducts were analyzed. Photochemical quantum yields, fluorescence quantum yields, and lifetimes of the excited singlet states were determined. The highest values of photochemical quantum yields (photo-S(N)1 mechanism) were obtained with caged cAMPs having a donor substituent in the 7-position of the coumarin moiety, caused by electronic stabilization of the intermediately formed coumarinylmethyl cation. With donor substitution in the 6-position, the resulting moderate electronic stabilization of the coumarinylmethyl cation is overcompensated by the strong bathochromic shift, reducing the energy gap between the excited-state S(1) and the corresponding coumarinylmethyl cation. The rate constant for the ester cleavage and liberation of cAMP is about 10(9) s(-1), estimated for the axial isomer of 6 by analysis of the fluorescence increase of the alcohol 12 formed upon laser pulse photolysis.     

Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by flavonoids from licorice roots and 4-arylcoumarins.

Isoliquiritigenin, glabridin, licoarylcoumarin and licoricidin were identified as strong inhibitors of adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase in waste materials which were obtained during the industrial extraction of glycyrrhizin from licorice roots. The structure-activity relationships of 12 flavonoids from licorice roots and 34 4-arylcoumarins were studied. In 4-arylcoumarins, 5,7-dihydroxy derivatives were generally highly inhibitory towards cAMP phosphodiesterase.     

On triazoles. XXII. Synthesis of Dialkyl (3-Q-1,2,4-triazol-5-yl)iminodithiocarbonates

Isomeric dialkyl and diaralkyl[1-, 2- and 4-(alkyl, aralkyl and aryl)-3-Q-1,2,4-triazole-5-yl]iminodithiocarbonates 4a-c (R ≠ H) were synthesised and their spectral data compared. The uv, cmr and ms rules elaborated helped to prove the tautomeric structure of the non-substituted derivatives 4 (R ? H). In case of dimethyl (3-methylthio-1,2,4-triazole-5-yl)iminodithiocarbonate this is the first time ever crystalline triazole desmotropes 4a/17 and 4b/17 could be isolated. The sodium salts of 4 (R ? H) could be further alkylated and aralkylated to yield the corresponding 4 (R ? alkyl and aralkyl) type derivatives. Providing the above reaction in the presence of carbon disulfide the dithiocarbomethoxy derivative 7 was obtained.     

Regioselective synthesis of novel N2- and N4-substituted 7-methylpyrazolo[4,5-e][1,2,4]thiadiazines

The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one1,1-dioxide (5) was synthesized and its novel mono N2- or N4-substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N2,N4-disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR,(1)H-NMR, (13)C-NMR and MS spectral analysis.     

Synthesis and computational studies of Mg complexes supported by 2,2':6,2'-terpyridine ligands

The reactions of the substituted 2,2':6,2'-terpyridine ligands, 4'-mesityl-2,2':6',2'-terpyridine (mesitylterpy) (1a), 4,4',4'-tri-tert-butyl-2,2':6',2'-terpyridine (tri-(t)Buterpy) (1b) and 4'-phenyl-2,2':6',2'-terpyridine (phenylterpy) (1c) with Grignard reagents were investigated. When half an equivalent of mesitylterpy or tri-(t)Buterpy were treated with MeMgBr in diethyl ether, the only products were (R-terpy)MgBr(2) (R = mesityl (5a), or tri-(t)Bu (5b)) and Me(2)Mg and a similar reaction was observed in THF. Compounds 5a and 5b were characterized by X-ray crystallography. Changing the Grignard reagent to PhMgBr also generated 5a and 5b along with Ph(2)Mg, while the reaction between MeMgCl or PhMgCl and 1a or 1b generated (R-terpy)MgCl(2) (R = mesityl (6a), or tri-(t)Bu (6b)) and either Me(2)Mg or Ph(2)Mg, respectively. The products from reactions between phenylterpy (1c) and Grignard reagents were highly insoluble and could not be fully characterized but appeared to be the same as those from reactions with 1a and 1b. In contrast to other studies using tridentate nitrogen ligands, which formed either mixed halide alkyl species or dihalide and bis(alkyl) species depending on whether the Grignard reagent was reacted with the ligand in diethyl ether or THF, the formation of mixed halide, alkyl complexes of the type (R-terpy)MgR'X (R' = Me or Ph; X = Cl or Br) or dialkyl species such as (R-terpy)MgR'(2) (R' = Me or Ph) was not observed here, regardless of the reaction conditions. DFT studies were performed to complement the experimental studies. The experimental results could not be accurately reproduced unless π-stacking effects associated with free terpyridine were included in the model. When these effects were included, the calculations were consistent with the experimental results which indicated that the formation of the terpy Mg dihalide species and R'(2)Mg (R' = Me or Ph) is thermodynamically preferred over the formation of mixed alkyl halide Mg species. This is proposed to be due to the increased steric bulk of the terpy ligand in the coordination plane, compared with other tridentate nitrogen donors.     

Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by flavonoids. III

Sixty-one flavanones, twenty-six isoflavones and eight other flavonoids, obtained from Sophora tomentosa, S. flavescens, Scutellaria baicalensis and other medicinal plants or synthesized, were tested for their inhibitory activity against adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase from beef heart. The structure-activity relationships were investigated.     

Synthesis of imidazoles as novel emivirine and S‐DABO analogues

5‐Alkyl‐4‐benzyl‐1,3‐dihydroimidazol‐2‐ones ( 3a‐d ) and 5‐alkyl‐4‐benzyl‐1,3‐dihydroimidazole‐2‐thiones (7a‐d) were prepared via Dakin West reaction on DL‐phenylalanine with the appropriate aliphatic acid anhydrides followed by hydrolysis and reaction with potassium cyanate or potassium thiocyanate. Compounds 3a‐d were alkylated with ethoxymethyl chloride to give the alkylated imidazoles 5a‐d which were considered analogues of Emivirine with deletion of carbonyl group at the 4‐position. Alkylation of 7a‐d afforded the corresponding S‐alkylated derivatives 8a‐p which in a similar way were considered analogues of S‐DABO. However all the imidazole derivatives were devoid of activity against HIV.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

Alkylation of Imidazolidinone Dipeptide Derivatives: Preparation of Enantiomerically Pure Di- and Tripeptides by ‘Chirality Transfer’ via a Pivalaldehyde N,N-Acetal Center. Preliminary Communication

Glycylglycine, glycyl-(S)-alanine, and (S)-alanylglycine esters are cyclized through pivalaldehyde imines to give dipeptide-derived 3-(benzyloxycarbonyl)-2-(tert-butyl)-5-oxoimidazolidine-1-acetates 1 – 3 . These are alkylated diastereoselectively by Li-enolate formation and addition of alkyl bromides or iodides (products 4 – 6 ). Starting from (S)-alanine and glycine, (S)-alanyl-(S)-alanine or (R)-alanyl-(R)-alanine, and (R)-alanyl-(R)alanyl-(S)-alanine- have thus been prepared, with the (tert-butyl)-substituted N,N-acetal center playing the role of a pivot or lever for diastereoselective formation of new stereogenic centers under kinetic or thermodynamic control.     

Syntheses of 4 and 5-alkylsulfonylimidazoles

A series of isomeric 4 and 5-alkylsulfonyl, alkylsulfinylimidazoles 9,10 were prepared by two general methods. Chlorosulfonation of imidazole afforded 4(5)-chlorosulfonylimidazoles 2, 4, 5 . The chlorosulfonyl derivatives were reduced, alkylated and oxidized to give 9 and 10 . In the second method 2, 4, 5 were converted to sodium sulfinate 8 and reacted with alkyl halides to afford the title compound 9 .     

Synthesis of derivatives of 4-alkylthiouracil,cytosine, pyrido[2,3-d]pyrimidine,and pyrimido[4,5-d]pyrimidine from the N,S- and N,N-acetals of diacetylketene and isocyanates

The action of alkyl and aryl isocyanates on the N,S-acetals of diacetylketene leads to the formation of 4-alkylthio-5-acetyl-1-alkyl(aryl)-6-methyl-1H-pyrimidin-2-ones (derivatives of 4-alkylthiouracils). The reaction of the synthesized thiouracils with amines or the reaction of the N,N-acetals of diacetylketene (N,N-ADK) with an equi-molar amount of aryl isocyanates leads to the formation of substituted 4-amino-5-acetyl-1H-pyrimidin-2-ones (derivatives of cytosine). From the latter and isocyanates or directly from N,N-ADK and an excess of the isocyanate, derivatives of 4-methylene-1H,3H, 4H-pyrimido[4,5-d]pyrimidine-2,7-dione were obtained. The exception was the condensation of 3-[N-(4,6-dimethyl-2-pyrimidinyl)diaminomethylene]pentane-2,4-dione with aryl isocyanates, which led to 3H,8H-pyrido[2,3-d]pyrimidine-2,5-diones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2593–2599, November, 1991.     

Synthesis and hypnotic activities of 4-thio analogues of N3-substituted uridines

Reaction of tri-O-acetyluridine (1) with benzyl bromide or 2-chloroacetophenone in the presence of K2CO3 gave the N3-substituted analogues 2a,c. Condensation of 1 with (+/-)-1-phenylethanol or 3,5-dimethylbenzyl alcohol using the Mitsunobu reaction also gave 2b,d in good yields. These compounds were allowed to react with Lawesson's reagent and were subsequently treated with ammonia to afford the 4-thiouracil derivatives 5a-d. Compounds 5a-c showed moderate hypnotic activity in mice. However, N3-(3,5-dimethyl)benzyl derivatives 3d, 5d were found to be almost inactive in this assay.     

New N6‐substituted 8‐alkyl‐2‐phenylmethylsulfanyl‐adenines. II

Title compounds bearing substituents on C(2), C(6) and C(8) were prepared from a newly synthesized pyrimidine derivative 11. The new pyrimidine 11 was generated from compound 2 through two different synthetic schemes. In one pathway, compound 2 was nitrosated, reduced and alkylated to produce com pounds 9 , 10 and 11 respectively (Scheme). In an alternate route using compound 2 as the starting material, a coupling reaction using the diazonium salt derived from p‐methylaniline afforded the azo derivative 7 , which was subsequently alkylated and reductively cleaved to form compounds 8 and 11 respectively (See Scheme). Compound 11 was annulated to the corresponding hypoxanthine derivatives 12–14 ; compounds 12 and 13 were chlorinated with phosphorus oxychloride, then reacted with amines to yield compound 17 and 20 respectively. Compounds 21 , 22 and 23 were obtained by oxidation of the corresponding sulfide as depicted in Scheme. Alkylation of the thiol function of 1 gave a mixture of 3 and 4. Compound 3 was chlo rinated to 5. Nitration of 5 resulted in electrophilic aromatic substitution of the aryl ring and concomitant oxidation of the sulfide to the sulfoxide, producing 6.