Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-2189.     

2-Phenylethyl ester and 2-phenylethyl amide derivative analogues of the C-terminal hepta- and octapeptide of cholecystokinin

Syntheses of analogues of the C-terminal octa- and heptapeptide of cholecystokinin are described. These analogues were obtained by replacing the C-terminal phenylalanine residue by 2-phenylethyl alcohol or by 2-phenylethylamine derivatives and by replacing the tryptophan residue by a D-tryptophan. The CCK-derivatives were tested for their ability to inhibit binding of labeled CCK-8 to rat pancreatic acini and to guinea pig brain membranes, and for their action on stimulation of amylase release from rat pancreatic acini. Some of these derivatives appeared to exhibit only part of the CCK-activity on amylase release, the D-Trp analogues behaving as CCK-antagonists.     

The mass spectra of the trimethylsilyl derivatives of cis- and trans- hexahydrocannabinol and their hydroxy and acid analogues

The mechanisms leading to the major ions in the mass spectra of the trimethylsilyl derivatives of cis- and trans-hexahydrocannabinol, five monohydroxy analogues, eight dihydroxy analogues, and two carboxylic acid derivatives were investigated with the aid of deuterium labelling and high resolution mass measurements.     

Pyrimidine arabinofuranosyl nucleosides with 5-substituted long, branched and unsaturated chains: synthesis and antiherpes properties

Several procedures have been applied to the preparation of 5-alkyl analogues of araU and araC via condensation of the appropriate 2,4-bis-O-(trimethylsilyl)-5-alkylpyrimidine with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride. The resulting O'-benzylated nucleosides were deblocked with the aid of BF3 . Et2O in C2H5SH. The araC analogues were also prepared by conversions of the corresponding 5-alkyl-araU derivatives. The chloromercuri derivatives of araU and araC, were reacted with allyl chloride in the presence of Li2PdCl4. The resulting 5-allyl derivatives were catalytically reduced to the corresponding 5-propyl analogues. Catalysed condensation of 2,4-bis-O-(trimethylsilyl)-5-vinyluracil with 2,3,5-tri-O-benzyl-alpha-D-arabinosyl chloride, as well as with 1-O-acetyl-2,3,5-tri-O-benzoylarabinofuranose, was carried out under a variety of different conditions. Deblocking of the benzylated nucleosides with various reagents led invariably to addition to the vinyl substituent. In the case of benzoylated nucleosides, deblocking yielded largely the alpha-anomers. The antiherpes activities of the 5-alkyl compounds have been evaluated, as well as the susceptibility of the araC analogues to enzymatic deamination.     

Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites

The rhodium(II)-catalyzed intermolecular C-H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described. The most notable compounds are the erythro-(2-naphthyl) analogues which display high binding affinity and selectivity for the serotonin transporter.     

Naphthalene combretastatin analogues: synthesis, cytotoxicity and antitubulin activity

Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimental for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.     

Synthesis and biological activity of 5-aza-ellipticine derivatives

Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.     

The synthesis of deuterium-substituted, spin-labeled analogues of AMP and NAD+ and their use in ESR studies of lactate dehydrogenase

Two spin-labeled analogues of AMP and NAD+ were synthesized, in which a perdeuterated nitroxide radical (4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, TEMPAMINE) was attached to C-6 or C-8 position of the adenine ring. The ESR spectra of these derivatives exhibit a 4-fold increase in sensitivity and a concomitant decrease in line-width as compared to the corresponding protonated analogues. The improved resolution of composite spectra consisting of freely tumbling and immobilized components is demonstrated in ternary complexes of the spin-labeled NAD+ derivatives with lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 1.1.1.27) and oxalate.     

Sensitivity of insect ovarian tissues to various pteridines as tested in tissue culture

The effect of pteridine derivatives and analogues on the cell outgrowth from the ovarian explants of the waxmoth, Galleria mellonella, was examined in hanging-drop cultures and cytochemical tests were made for succinate and glucose-6-phosphate dehydrogenases. Most of the derivatives and analogues of 2-amino-4-hydroxypteridine injured to a lesser or greater extent insect ovarian tissues in vitro, depending on the drug structure and the concentration applied. Of all the pteridine derivatives and analogues tested only 2-amino-4-mercaptopteridine and its C-6,7-dimethyl derivative (10 μM) promoted cell outgrowth from the explants as did folate.     

Synthesis and evaluation of phenylcarbamate derivatives as ligands for nicotinic acetylcholine receptors

Phenylcarbamate derivatives were synthesized and evaluated in radioligand binding assays for different nicotinic acetylcholine receptor (nAChR) subtypes. Carbamate derivatives bearing a pyrrolidine or piperidine moiety 8-20 exhibited much lower affinity for alpha7* nAChR than the analogues in the quinuclidine series 21-25, although the same structural elements are present. Furthermore, in contrast to the quinuclidine analogues 21-25, all (S)-pyrrolidine derivatives 8-12 and the piperidine analogues 15 and 16 exhibited higher affinities for alpha4beta2* nAChR.     

Review ArticleNaphthalene Combretastatin Analogues: Synthesis,Cytotoxicity and Antitubulin Activity

Synthesis and evaluation of new combretastatin analogues with varied modifications on the bridge and the aromatic rings, have shown that the 2-naphthyl moiety is a good surrogate for the 3-hydroxy-4-methoxyphenyl (B-ring) of combretastatin A-4. Other bicyclic systems, such as 6(7)-quinolyl and 5-indolyl, can replace the B-ring, but they produce less potent analogues in the cytotoxicity and tubulin polymerization inhibition assays. Other modifications are detrimentral for the potency of the studied analogues. The 2-naphthyl combretastatin 53 and the related 6-quinolyl combretastatin 106 analogues are the most potent among the derivatives of this type, whereas 92 and 95 are the most potent among the naphthalene derivatives with a heterocycle in the bridge. Previous and new results in this family of combretastatin analogues are discussed.     

Synthesis and evaluation of a series of tropane analogues as novel vesicular monoamine transporter-2 ligands

A series of tropane derivatives has been synthesized as lobelane analogues and evaluated for their binding affinity at the vesicular monoamine transporter-2 (VMAT2), and at alpha4beta2* and alpha7* nicotinic acetylcholine receptors. The trop-2-ene analogues 4a and 4b exhibited good affinity and high selectivity for VMAT2.     

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.     

Achievements and prospects of the directed search for antiviral agents in the nucleoside series and their derivatives]

Recent advances of antiviral drug design among nucleosides and their derivatives have been summarized. The first chapter deals with the history of nucleic acids components and further developments in this area. Next part discusses the mechanism of action of biologically active nucleosides: 2',3'-dideoxynucleosides, acyclic analogues, phosphonate derivatives and nucleoside antibiotics. The third chapter describes planning of complicated synthesis of nucleoside analogues from branched-chain sugars and stereo-specific formation of glycosidic bond upon synthesis of ribonucleoside and 2'-deoxyribonucleoside. The last part outlines further perspectives, i. e. preparation of antiviral compounds and use of nucleoside analogues in oligonucleotide synthesis.     

Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors

Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.     

Structure-antiemetic-activity of some diarylheptanoids and their analogues

The structure-activity relationship of diarylheptanoids and their analogues inhibitory of emesis induced by copper sulfate in young chicks was investigated by testing 19 compounds. The compounds are 5 diarylheptanoids isolated from Alpinia katsumadai (Zingiberacea), 5 chemical derivatives of them, 6 analogues isolated from Zingiber officinale rhizome (Zingiberaceae), and 3 analogues available on the market. Among them, two types of essential functional structure of diarylheptanoids and their analogues showed the inhibitory effects against emesis.     

The chemical synthesis and cytotoxicity of new sulfur analogues of 2-methoxy-lysophosphatidylcholine

The chemical synthesis of phosphorothioate/phosphorodithioate analogues of 2-methoxy-lysophosphatidylcholine has been described. For the preparation of new sulfur derivatives of lysophosphatidylcholine both oxathiaphospholane and dithiaphospholane approaches have been employed. Each lysophospholipid analogue was synthesized as a series of five compounds, bearing different fatty acid residues both saturated (12:0, 14:0, 16:0, 18:0) and unsaturated (18:1). The methylation of glycerol 2-hydroxyl function was applied in order to increase the stability of prepared analogues by preventing 1→2 acyl migration. The cellular toxicity of newly synthesized 2-methoxy-lysophosphatidylcholine derivatives was measured using MTT viability assay and lactate dehydrogenase release method.     

Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies

Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-alpha analogues bearing different methyl substituted phenyl ketone groups at the N3-position of the 2-iminothiazole heterocycle. From stability studies in a biological medium as well as under specific chemical conditions, we have shown by NMR techniques that through a dehydration process, some derivatives can generate their corresponding cyclized analogues. All of the new analogues, Pifithrin-like and polycyclic dehydrated derivatives were assessed for their p53 inactivation potency by measuring survival of cortical neurons, whose death was induced by the DNA-damaging agent etoposide. Pifithrin-alpha like 2f as well as the cyclic dehydrated 6b analogue were found to be one log more potent p53 inactivators than reference compound Pft-alpha, with EC50 values ranging around 30 nM. These results support the finding that p53 inactivation by Pft-alpha analogues could be also due to the presence of the cyclic dehydrated Pft-alpha forms, generated in situ in the biological assay incubation medium.     

Design and SAR study of a novel class of nucleotide analogues as potent anti-HCMV agents.

We have developed a novel class of 2-phosphonate 1,3-dioxolane nucleotide analogues, from which the guanine derivative displayed weak anti-HCMV activity. Further SAR studies led to the identification of both cis and trans guanine derivatives of tetrahydrofuran analogues as potent anti-HCMV agents, both in vitro and in vivo, compared to ganciclovir and HPMPC.     

Syntheses of the 3- and 4-thio analogues of 4-nitrophenyl 2-acetamido-2-deoxy-beta-D-gluco- and galactopyranoside

The syntheses of 4-nitrophenyl beta-glycosides of the 3-thio and 4-thio analogues of the two principal 2-acetamido-2-deoxy-hexoses found in living systems, GlcNAc and GalNAc, are described. While synthesis of the 4-thio analogues could be achieved via nucleophilic displacements of sulfonate derivatives with thioacetate, problems with neighbouring group acetamido participation necessitated the use of sulfamidate intermediates for the 3-thio analogues. These 3- and 4-thio analogues are employed in the chemo-enzymatic synthesis of thio-oligosaccharide analogues of structures present in glycosaminoglycans, glycoproteins and glycolipids.