Synthesis and biological evaluation of new muscarinic receptor antagonists bearing cyclic amidines as cationic heads

Two classes of compounds, bearing a cyclic amidino moiety instead of the tertiary amino group of the classical antimuscarinic drugs like hexahydrodifenidol 3 were synthesized. Affinities (KD) for the three pharmacologically defined M1, M2 and M3 mAChR subtypes were measured in radioligand binding assays and in functional in vitro studies (KB) in guinea pig ileum and left atrium. The results showed that the replacement of the tertiary amino group in structural analogues of 3 with a cyclic amidino moiety afforded potent antimuscarinic compounds. The selectivity shown for smooth muscle preparations suggests their usefulness as antispasmodics.     

Synthesis and biological evaluation of new cyclic amidine analogs of chlorambucil

A number of novel cyclic amidine analogs of chlorambucil were synthesized and examined for cytotoxicity in breast cancer cell cultures and for inhibition of topoisomerases I and II. Evaluation of the cytotoxicity of these compounds employing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and inhibition of [(3)H]-thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more active than chlorambucil. The degree to which these compounds inhibited cell growth breast cancer cells was directly correlated to DNA-binding affinity. These studies indicate that cyclic amidine analogs of chlorambucil are a potent catalytic inhibitor of topoisomerase II but not topoisomerase I. The highest degree of DNA binding and cytotoxicity in both MDA-MB-231 and MCF-7 breast cancer cells was observed for the compound, which possess a 4,5-dihydro-1H-imidazol moiety.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

Synthesis and biological evaluation of new niphathesine analogues

Niphathesine C and related pyridine alkaloids are well known natural products with interesting antimicrobial activities, characterized by a pyridine ring and a lipophilic side chain with a terminal nitrogen-containing functional group. This paper describes the synthesis of analogues of these alkylpyridine alkaloids with variation of the heterocyclic ring and the terminal functional group. Key steps of the syntheses are a Sonogashira reaction of appropriate aryl iodides with undec-10-ynol or undec-10-ynoic acid derivatives. The resulting compounds were tested in an agar diffusion assay against several bacteria and fungi.     

Synthesis of new compounds with local anesthetic activity. 11. Synthesis and action of 4-(3-bibenzyl-4-yl-propyl)-morpholine, a bioisosteric fomocaine

Syntheses of New Compounds with Local Anaesthetic Activity, XI: Synthesis and Activity of 4-(3-Bibenzyl-4-yl-propyl)-morpholine, a Bioisosteric Fomocaine 4-(3-Bibenzyl-4-yl-propyl)-morpholine ( 1 ) was prepared by 3 routes. Optimum yield (35% over 3 steps) is achieved by acylation of 4 , amination of 3 and hydrogenation of 5 . With regard to surface anaesthesia and approx. DL₅₀, 1 cannot be compared to fomocaine. This is the first case in the group of fomocaines that –O– and –CH₂– are not bioequivalent as the rule of bioisosterism demands.     

Synthesis and biological action of the aminotetrahydroisoquinocarbazoles and related compounds: a new class of compounds with antiarrhythmic activity.

A series of 12-aminotetrahydroisoquinocarbazoles and related compounds were synthesized using an intramolecular Diels-Alder reaction and screened for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice. Several compounds showed more potent activity than disopyramide. There was some correlation between substituents on aromatic ring and angular position, and antiarrhythmic activity. An amino group or some functional groups containing an amino group on C-12 seemed to be essential to exhibit the activity. Ring size also influenced the activity. The compound (+)-10 (RS-2135) had the most favorable combination of antiarrhythmic activity and toxicity and was selected for further evaluation.     

Synthesis and biological evaluation of 14-alkoxymorphinans. 3. Extensive study on cyprodime-related compounds

A series of cyprodime-related compounds (2, 4-12, and 26) has been synthesized and evaluated for opioid agonist and antagonist activity with the mouse vas deferens and guinea pig ileum preparations. None of the changes to cyprodime, including the introduction of a 3-OMe group, increasing and decreasing the size of or completely removing the substituent in position 4, replacing the N-cyclopropylmethyl group with an N-allyl group, or replacing the 14-OMe with an 14-OEt substituent, resulted in an improved mu antagonist profile and most were detrimental either in terms of mu selectivity and potency or increased agonist activity. Increasing the length of the substituent in position 4 resulted in a compound (6a) with a very similar profile to that of cyprodime.     

A new synthesis of carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs.

A new synthesis of carboxyterfenadine (4), based on the conversion of a alpha-halo-alkylarylketone into the corresponding substituted 2-arylalkanoic ester, is described. The enantioselective synthesis of its two bioisosteric tetrazole analogs together with preliminary biological results are reported.     

Methotrexate analogues. 28. Synthesis and biological evaluation of new gamma-monoamides of aminopterin and methotrexate

Lipophilic gamma-monoamide derivatives of aminopterin (AMT) were synthesized in high overall yield from 4-amino-4-deoxy-N10-formylpteroic acid and gamma-N-tert-alkyl-, gamma-N-aralkyl-, or gamma-N-arylamides of alpha-benzyl L-glutamate via a modification of the mixed carboxylic-carbonic anhydride coupling method. Coupling was also accomplished with p-nitrophenyl 4-amino-4-deoxy-N10-formylpteroate. Compounds obtained in this manner included the gamma-tert-butylamide, gamma-(1-adamantylamide), gamma-benzylamide, gamma-(3,4-dichlorobenzylamide), gamma-(2,6-dichlorobenzylamide), gamma-anilide, gamma-(3,4-methylenedioxyanilide), and gamma-(3,4-dihydroxanilide) derivatives of AMT. Also prepared, from 4-amino-4-deoxy-N10-methylpteroic acid via diethyl phosphorocyanidate coupling, was the gamma-(3,4-methylenedioxyanilide) of MTX. The methylenedioxyanilides were cleaved smoothly to dihydroxyanilides with boron tris(trifluoroacetate) in trifluoroacetic acid. All the gamma-monoamides were tested as inhibitors of purified dihydrofolate reductase (DHFR) from murine L1210 leukemia cells and as inhibitors of the growth of wild-type L1210 cells and a subline (L1210/R81) with high-level resistance to MTX and AMT based mainly on a defect in drug uptake via active transport. Several compounds were also tested against human leukemic lymphoblasts (CEM cells) and a resistant subline (CEM/MTX) whose resistance is likewise based on uptake. The IC50 of the gamma-monoamides against DHFR was 1.5- to 5-fold higher than that of the parent acids, but the IC50 against cultured cells varied over a much broader range, suggesting that uptake and/or metabolism rather than DHFR binding are principal determinants of in vitro growth inhibitory activity for these compounds. gamma-N-Aryl and gamma-N-aralkyl derivatives appeared to be more potent than gamma-N-tert-alkyl derivatives. Where comparison could be made, AMT gamma-monoamides were more potent than MTX gamma-monoamides. Several of the gamma-monoamides showed potency comparable to that of the parent acid against wild-type L1210 and CEM cells; all of them were more potent than MTX against the L1210/R81 subline; and some of the AMT gamma-monoamides were also more potent than the parent acid against resistant CEM/MTX cells. As a group, however, the gamma-monoamides were considerably more active against the murine cells than against the human cells, suggesting that the former may take up the amides better or may be able to metabolize them more efficiently than the parent acids. All the gamma-monoamides were tested in vivo against L1210 leukemia in mice.(ABSTRACT TRUNCATED AT 400 WORDS)     

Synthesis and biological evaluation of some new 3 ,4-dihydropyrimidin-4-ones.

Condensation of 5-cyano-2-hydrazino-3-N-methyl-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (3a and 3b) with 2,4-bisalkyl/arylamino-6-chloro-s-triazine (4) gave the corresponding 2,4-bisalkyl/arylamino-6-[5'-cyano-3'-N-methyl]-6'-phenyl/pchlorophenyl-3',4'-dihydropyrimidin-4'-one-2'-yl-hydrazino-s-triazines (5a-n and 6a-n). The compounds 4 have been prepared by the condensation of cyanuric chloride and different alkyl/aryl amines. The reaction between 5-cyano-3-N-methyl-2-methylthio-6-phenyl/p-chlorophenyl-3,4-dihydropyrimidin-4-one (2a and 2b) with hydrazine hydrate furnished 3a and 3b, respectively. The condensation of 6-phenyl/p-chlorophenyl/5-cyano-2-mercapto-3,4-dihydropyrimidin-4-one (1a and 1b) with methyl iodide yielded 2a and 2b, respectively. All the products have been evaluated in vitro for their antimicrobial activity against several microbes and antitubercular activity against Mycobacterium tuberculosis H37 Rv.     

Synthesis and biological evaluation of pseudostellarin B.

A new potent bioactive cyclic peptide pseudostellarin B has been synthesised. The structure was elucidated by elemental analyses, IR, 1H NMR, 13C NMR and FAB mass spectral data. The synthesised compound was also screened for its antibacterial, antifungal, antiinflammatory and anthelmintic activities.     

Synthesis and biological evaluation of new pentaphyrin macrocycles for photodynamic therapy

This paper describes the synthesis and in-depth characterization of two new porphyrogenic macrocycles 1 and 2, and provides an evaluation of these molecules as photosensitizer agents. By tuning the reaction conditions and starting from readily available 1,9-diformyl-5-phenyldipyrromethane (4) and tripyrrane dicarboxylic acid (3), both the nonaromatic isopentaphyrin 1, composed of a 24 pi-electron macrocycle, and the aromatic pentaphyrin 2, composed of a 22 pi-electron macrocycle, were obtained in good yield and purity. Confocal laser microscopy and cytofluorimetry studies showed that the newly synthesized pentaphyrins penetrate the cell membranes and localize mainly in the cytoplasm. In the absence of light, 1 and 2 exhibit a nonsignificant cytotoxic effect at concentrations up to 3 mug/mL. In contrast, the synthesized pentaphyrins, when delivered to cells at 1.5 or 3 microg/mL and irradiated with white light (8 mW/cm(2)), promoted a strong and dose-dependent phototoxic effect in four different cell lines. FACS and caspase-3/7 activation assays demonstrated that the pentaphyrins cause cell death by apoptosis.     

Physicochemical and biological evaluation of cationic polymethacrylates as vectors for gene delivery.

We report here the physicochemical and biological evaluation of a series of polymethacrylates with side groups of different pK(a) values, such as tertiary amines, pyridine groups, acid functions and imidazole groups as synthetic vectors for gene delivery. The ability of the different polymers to condense DNA was studied by ethidium bromide exclusion tests and agarose gel electrophoresis. The results show that all polymers are able to condense DNA. Both the molecular weight and the chemical composition of the polymers have an influence on the DNA condensation process. Furthermore, the biological properties of the polymer-DNA complexes were investigated, including their haemolytic activity, cytotoxicity and in vitro transfection efficiency. Complexes based on polymers containing only tertiary amines, have a transfection efficiency similar to that of poly(ethyleneimine) (PEI). Polymers containing pyridine groups have a reduced transfection efficiency compared to polymers containing tertiary amines. Introduction of imidazole groups or acid functions results in a loss of the transfection efficiency of the corresponding complexes with DNA. In general, the viability of cells incubated with complexes based on the polymethacrylates is higher than with PEI. Polymers with high transfection efficiency induce erythrocyte lysis.     

Synthesis and biological evaluation of bilobol and adipostatin A

Concise total synthesis of bilobol 5-pentadecenylresorcinol (1), isolated from Gingko biloba fruits, has been achieved in 10 steps with 51% overall yield from 3,5-dihydroxybenzoic acid (3). Adipostatin A (2), isolated from the fruits as well as from Streptomyces cyaneus 2299-SV1, has also been synthesized in two steps from methylated bilobol (10). The structure-activity relationship study of synthetic products was described by means of cytotoxic assay against human KB carcinoma cell lines.     

Synthesis and biological evaluation of bilobol and adipostatin A

Concise total synthesis of bilobol 5-pentadecenylresorcinol (1), isolated from Gingko biloba fruits, has been achieved in 10 steps with 51% overall yield from 3,5-dihydroxybenzoic acid (3). Adipostatin A (2), isolated from the fruits as well as from Streptomyces cyaneus 2299-SV1, has also been synthesized in two steps from methylated bilobol (10). The structure–activity relationship study of synthetic products was described by means of cytotoxic assay against human KB carcinoma cell lines.     

Synthesis and biological evaluation of 4-purinylpyrrolidine nucleosides.

The synthesis of several novel carbocyclic purine nucleosides that incorporate a nitrogen in place of carbon 3 of the cyclopentyl moiety are described. These analogues are all derived from the key stereochemically defined intermediate N-(tert-butoxycarbonyl)-O-[(4-methoxyphenyl)diphenylmethyl]-trans- 4- hydroxy-D-prolinol (19), which was accessible in 61.1% overall yield for a five-step sequence starting from cis-4-hydroxy-D-proline. The heterocyclic bases, 6-chloropurine and 2-amino-6-chloropurine, are efficiently introduced onto the pyrrolidine ring via a Mitsunobu-type coupling procedure with triphenylphosphine and diethyl azodicarboxylate. Standard transformations and removal of protecting groups gave the cis-adenine (26), hypoxanthine (27), 2,6-diaminopurine (28), and guanine (29) D-prolinol derivatives. In addition, a related sequence from trans-4-hydroxy-L-proline provided the enantiomeric L-prolinol guanine derivative (36). Lastly, the 6-(dimethylamino)purine analogue, 37, was coupled to N-(benzyl-oxycarbonyl)-p-methoxy-L-phenylalanine to provide, after deprotection, the novel puromycin-like analogue 39. The analogues 26-29, 36, and 39 were all evaluated for antitumor and, except for 39, for antiviral activity. These compounds failed to appreciably inhibit the growth of P388 mouse leukemia cells in vitro at concentrations up to 100 micrograms/mL. In addition, they did not exhibit noticeable activity against the human immunodeficiency virus or herpes simplex virus type 1 at concentrations as high as 100 microM. The adenine analogue, 26, did, however, prove to be a substrate for adenosine deaminase. It possessed an affinity for the enzyme only 50% less than that of adenosine with a Ki = 85 microM.