Application of a 6pi-1-azatriene electrocyclization strategy to the total synthesis of the marine sponge metabolite ageladine A and biological evaluation of synthetic analogues

A 12-step synthesis of the angiogenesis inhibitory marine metabolite ageladine A is reported. The key steps include a 6pi-1-azatriene electrocyclization for formation of the pyridine ring and a Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloroimidazopyridine. In addition, an assessment of the biological activity of a variety of synthetic analogues of ageladine A prepared during this synthesis is described.     

Chemical synthesis and biological properties of pyridine epothilones

BACKGROUND: Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors. RESULTS: A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus. CONCLUSIONS: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified.     

Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.     

Synthesis of N-benzyl-des-D-ring lamellarin K via an acyl-Claisen/Paal-Knorr approach

Lamellarin K is a complex pyrrole natural product and member of the lamellarin family – a group of natural products known for their potent biological activities, such as, antiproliferative activity and inhibition of P-gp mediated drug efflux pumps. We herein describe the synthesis of the N-benzyl-des-D ring analogue of lamellarin K using a route that centres on an acyl-Claisen reaction to eventually prepare a highly-functionalised 1-aryl-4-methyl-1,4-diketone. Paal-Knorr pyrrole formation using this diketone undergoes auto-oxidation to give a fully-substituted 5-formyl pyrrole which was converted into the natural lactone B ring. Antiproliferative testing of the N-benzyl-des-D ring analogue gave an IC₅₀ of 2.63 μM against the MDA-MB-231 breast cancer cell line.     

Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities

A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.     

Using of 4-amino-2-phenylindoles in the synthesis of pyrroloquinolines by the combes reaction

The reaction of 4-amino-2-phenyl- and 4-amino-l-methyl-2-phenylindoles with a free β-position of the pyrrole ring with acetylacetone and dibenzoylmethane was studied. It was found that primary condensation occurs only on aminogroups and produces the corresponding enaminoketones, which under conditions of enamine acidic cyclization on the basis of dibenzoylmethane, turn into pyrrolo[2,3-h]-quinolines. The products of cyclization with participation of indole 3 atom were not detected.     

Synthesis and platelet aggregation inhibitory activities of 3-(2-oxopropylidene)azetidin-2-one derivatives. II.

A series of 3-acylidene-4-methylazetidin-2-one derivatives bearing various substituents at the 1-position of the azetidin-2-one ring was synthesized. These compounds were evaluated for platelet aggregation inhibitory activities. Most of the compounds synthesized showed potent inhibitory activities against rabbit platelet aggregation induced by adenosine diphosphate or collagen in vitro. Structure-activity relationships are also discussed.     

Influence of ring substitution on the conformation and β-turn mimicry of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one peptide mimetics

Analogs of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-ones, containing a methyl substituent at the 4- or 5-position, or a phenyl substituent at C-1, were prepared. Conformational analysis of tetrapeptide models containing these analogs indicated different conformations of the benzazepinone ring, and extended backbone conformations, except for the 4-methyl-substituted analog. The latter was shown to have a strong preference for a turn conformation. Incorporation into the N-terminal tetrapeptide sequence of dermorphin resulted in potent opioid analogs and an indication that the receptor-bound conformation might not adopt a turn structure.     

Synthesis and CDK2 kinase inhibitory activity of 7/7′-azaindirubin derivatives

A series of novel 7′-azaindirubin (1a-g) and 7-azaindirubin (2a, 2c, 2e and 2f) derivatives were designed and synthesized. Their structures were characterized by 1H NMR and MS spectroscopy as well as by elemental analysis. Their inhibitory properties against CDK2/cylinA were evaluated in vitro. In contrast to indirubin, some of the described azaindirubins emerged as potent inhibitors of CDK2/cylinA and compound 2b had more potent activity. Biological tests also showed that nitrogen atom at 7-position of azaindirubin was more beneficial to enhance the kinase inhibitory activity.     

Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.     

Constructing sandwich-type rare Earth double-decker complexes with N-confused porphyrinato and phthalocyaninato ligands

Reaction of the half-sandwich complexes M(III)(Pc)(acac) (M = La, Eu, Y, Lu; Pc = phthalocyaninate; acac = acetylacetonate) with the metal-free N-confused 5,10,15,20-tetrakis[(4-tert-butyl)phenyl]porphyrin (H(2)NTBPP) or its N2-position methylated analogue H(CH(3))NTBPP in refluxing 1,2,4-trichlorobenzene (TCB) led to the isolation of M(III)(Pc)(HNTBPP) (M = La, Eu, Y, Lu) or Y(III)(Pc)[(CH(3))NTBPP] in 8-15% yield. These represent the first examples of sandwich-type rare earth complexes with N-confused porphyrinato ligands. The complexes were characterized with various spectroscopic methods and elemental analysis. The molecular structures of four of these double-decker complexes were also determined by single-crystal X-ray diffraction analysis. In each of these complexes, the metal center is octa-coordinated by four isoindole nitrogen atoms of the Pc ligand, three pyrrole nitrogen atoms, and the inverted pyrrole carbon atom of the HNTBPP or (CH(3))NTBPP ligand, forming a distorted coordination square antiprism. For Eu(III)(Pc)(HNTBPP), the two macrocyclic rings are further bound to a CH(3)OH molecule through two hydrogen bonds formed between the hydroxyl group of CH(3)OH and an aza nitrogen atom of the Pc ring or the inverted pyrrole nitrogen atom of the HNTBPP ring, respectively. The location of the acidic proton at the inverted pyrrole nitrogen atom (N2) of the protonated double-deckers was revealed by (1)H NMR spectroscopy.     

Synthesis of non-THF analogs of acetogenin toward simplified mimics

Acetogenin analogs in which the bis-adjacent THF ring was replaced with an enantioselectively synthesized 1,2-cyclopentanediol bis-ether skeleton were synthesized to obtain simplified mimics, and their inhibitory effect on mitochondrial NADH-ubiquinone oxidoreductase (complex I) was examined. The results clearly demonstrate that the 1,2-cyclopentanediol bis-ether motif can substitute for the bis-THF ring while maintaining very potent inhibitory activity at the nanomolar level.     

Synthesis and CDK2 kinase inhibitory activity of 7/7′-azaindirubin derivatives

<正>A series of novel 7'-azaindirubin(1a-g) and 7-azaindirubin(2a,2c,2e and 2f) derivatives were designed and synthesized.Their structures were characterized by ~1H NMR and MS spectroscopy as well as by elemental analysis.Their inhibitory properties against CDK2/cylinA were evaluated in vitro.In contrast to indirubin,some of the described azaindirubins emerged as potent inhibitors of CDK2/cylinA and compound 2b had more potent activity.Biological tests also showed that nitrogen atom at 7-position of azaindirubin was more beneficial to enhance the kinase inhibitory activity.     

Fused isoquinolines: 3-aryl-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione-2-spiro-4′-(1′-alkyl-1′,4′-dihydropyridine)s

Previously unknown 3-arylamino-1,2-dihydro-1-isoquinolones were obtained by condensation of 2-cyanomethylbenzoic acid with arylamines. Isonicotinoylation of the compounds was shown to proceed at the carbon atom in the 4-position to give 3-arylamino-4-isonicotinoyl-1,2-dihydro-1-isoquinolones which were quaternized with alkylating agents and formed the corresponding pyridinium salts. Deprotonation of the latter induced intramolecular conjugated addition with the pyrrole ring closure and formation of spiro compounds. The structure of the products was confirmed by NMR, IR and UV spectroscopy and by synthesis of the model compound, 3-(4-tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione.     

Application of the Mössbauer spectroscopy to the study of the oxidation state of azaferrocene derivatives

Azaferrocene has two active sites of iron and nitrogen atoms. Drastic change of the oxidation state in iodine oxidation of azaferrocene is observed by introducing the methyl substituents into the pyrrole ring, while all the N-methylates show a similar electronic state. It was revealed that an introduction of methyl substituent to the pyrrole ring promotes the oxidation of nitrogen atom in pyrrole ring more than the central iron atom.     

The application of vinylogous iminium salt derivatives to an efficient relay synthesis of the pyrrole containing alkaloids polycitone A and B

A new and efficient relay synthesis of the marine natural products polycitone A and B is described. The new strategy relies on the formation of 2,4-disubstituted pyrroles from a vinamidinium salt followed by electrophilic substitution at the 5-position of the pyrrole and Suzuki coupling at the 4-position to produce the tetrasubstituted heterocycle efficiently and with complete control of regiochemistry.     

Effect of stereochemistry of Δlac-acetogenins on the inhibition of mitochondrial complex I (NADH-ubiquinone oxidoreductase)

Δlac-Acetogenins are a new type of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). We synthesized a series of Δlac-acetogenins in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was systematically modified, and examined their inhibitory effect on complex I. The present results revealed that the inhibitory effects of the bis-THF ring analogs are much more potent than those of the mono-THF ring analogs and that the stereochemistry around the bis-THF ring moiety significantly influences the inhibitory effect. The profiles of the structure-activity relationship observed for Δlac-acetogenins were entirely different from those for natural-type acetogenins.     

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.     

A new and convergent synthesis for 2,5-diamino-tetrahydropyrimidones

AN1057A/B has shown potent activity against MRSA. A novel and concise route to the synthesis of its heterocycle core 2,5-diamino-5,6-dihydro-1H-pyrimidine-4-one is described. This methodology allows the synthesis of an array of analogs with different amine substitutions at the 2-position.     

Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.