Showing papers on "Bicyclic molecule published in 1994"

Advantageous applications of azabenzotriazole (triazolopyridine)-based coupling reagents to solid-phase peptide synthesis

Abstract: 1-Hydroxy-7-azabenzotriazole (HOAt) and its corresponding uronium and phosphonium salts are shown to be superior to their benzotriazole analogs in solid-phase peptide synthesis, thereby making possible the automated synthesis of peptides containing hindered amino acids.

Catalytic Ring Closing Metathesis of Dienynes: Construction of Fused Bicyclic [n.m.0] Rings

Abstract: Ruthenium carbene 1 (Cl2(PCy3)2RuCHCHCPh2) mediates the efficient and selective conversion of acyclic dienynes to fused bicyclic [n.m.0] rings containing five-, six-, and seven-membered rings. Studies with various X-substituted acetylenes (X = H, alkyls, Ph, CO2Me, SnBu3, TMS, Cl, Br, I) suggest that the dienyne metathesis is sensitive not only to these substituents but also to the catalysts employed. Among the various metal alkylidenes examined, only the ruthenium catalyst 1 exhibited metathesis activity for a range of substrates. These observations further expand the scope of catalytic RCM for the construction of complex organic compounds.

FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination.

Abstract: The structure of FR901228 (C 24 H 36 N 4 O 6 S 2 ), including stereochemical details, was determined by a combination of spectroscopic, chemical evidence and single-crystal X-ray crystallographic analysis using anomalous dispersion from the S atoms

Synthesis of novel N-phosphonoalkyl dipeptide inhibitors of human collagenase

Abstract: The synthesis of a series of N-phosphonalkyl dipeptides 6 is described. Syntheses were devised that allowed the preparation of single diastereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of radiolabeled collagen by purified human lung fibroblast collagenase. Several of the compounds were potent collagenase inhibitors and were at least 10-fold more potent than their corresponding N-carboxyalkyl analogues. Activity was lost when the phosphonic acid group P(O)(OH)2 was replaced by the phosphinic acid groups P(O)(H)(OH) and P(O)(Me)(OH). At the P1 position, (R)- or (S)-alkyl groups, especially ethyl and methyl (e.g., 12a,b, 52a,b, and 53a,b), or an (R)-phenethyl moiety (55a) conferred high potency (IC50 values in the range 0.23-0.47 microM). (S)-Stereochemistry was preferred for the P1' isobutyl side chain. Structure-activity relationships were also investigated at the P2' site, and interestingly, compounds with basic side chains, such as the guanidine 57a, were equipotent with more lipophilic compounds, such as 52a. As with other series of collagenase inhibitors, potency was enhanced by introducing bicyclic aromatic P2' substituents. The most potent phosphonic acid of the series was the bicyclic aromatic P2' tryptophan analogue 59a (IC50 0.05 microM).

Total Synthesis and Determination of the Absolute Configuration of Epibatidine

Abstract: The synthesis of (+)- and (-)-epibatidine (exo-2-(2-chloropyridin-5-yl)-7-azabicyclo[2.2.1]heptane) via reaction of 5-lithio-2-chloropyridine with (+)- and (-)-N-BOC-7-azabicyclo [2.2.1]heptan-2-one is described. The absolute configuration of the natural product is shown to be 1R,2R,4S

Improved Fischer Indole Reaction for the Preparation of N,N-Dimethyltryptamines: Synthesis of L-695,894, a Potent 5-HT1D Receptor Agonist

Abstract: Among biologically active indoles, tryptamines show tremendous central nervous system activity. For example, the neurotransmitter serotonin (2) [5-hydroxytryptamine (5-HT)l is involved in the regulation of various physiological functions, such as appetite, sleep, body temperature, blood pressure, and sexual behavior;l its N,Ndimethyl analogue bufotenine (3) is a hallucinogen. The N,N-dimethyltryptamines also act as ~ H T ~ D agonists and possess great potential for the treatment of migraine. Sumatriptan (4) is the first of this class of drugs to be approved for this use.2 L-695,894 (11, which contains the 3-amino-1,2,4-oxadiazole heterocycle instead of a sulfonamide, is also a potent ~-HTID agonist that is a potential agent for migraine the rap^.^ We now wish to disclose a highly efficient method for the preparation of N,Ndimethyltryptamines with application to the synthesis of L-695,894 (1).

Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors.

Abstract: A variety of analogues of 1-[4-methoxy-3,56-dimethylbenzyl]-4-[3-(ethylamino)-2-pyridyl]piperazine hydrochloride (U-80493E) were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Replacement of the substituted aryl moiety with various substituted indoles provided bis(heteroaryl) piperazines (BHAPs) that were 10-100-fold more potent than U-80493E. The pyridyl portion of the lead molecule was found to be very sensitive to modifications. Extensive preclinical evaluations of several of these compounds led to the selection of 1-[(5-methoxyindol-2-yl)carbonyl]-4-[3-(ethylamino)-2-pyridyl]piperazine methanesulfonate (U-87201E, atevirdine mesylate) for clinical evaluation

Tautomerism N(9)H .dblharw. N(7)H of Purine, Adenine, and 2-Chloroadenine: Combined Experimental IR Matrix Isolation and Ab Initio Quantum Mechanical Studies

Abstract: The combined IR matrix isolation and ab initio HF/6-31G(d,p) studies have been performed to reexamine the vibrational IR spectra of purine, adenine, and 2-chloroadenine and to conclude about the N(7)N⇄N(9)H tautomerism of these purines. We present new evidence to prove that the N(9)H tautomeric forms (amino for adenines) of isolated species in question are highly dominant. This conclusion is also in agreement with the predicted relative energies of the N(7)H and N(9)H tautomers based on the electronic energies calculated at the MP2(full)/6-31G(d,p)//HF/6-31G(d,p) level and zero-point vibrational energies from the HF/6-31G-(d,p) calculations (the total relative energies are 15.1, 32.4, and 33.9 kJ/mol, in favor of the N(9)H tautomers of purine, adenine, and 2-chloroadenine, respectively)

Synthesis of Several Isomeric Tetrathiafulvalene .pi.-Electron Donors with Peripheral Sulfur Atoms. A Study of Their Radical Cations

Abstract: An efficient synthesis of one new (10) and three previously reported (9, 11, and 12) π-electron donors, which have one sulfur atom in each of the outer five-membered rings attached to the TTF system, is presented. The radical cations derived from (9-11) have been studied by ESR spec- troscopy and the spin density distribution of these radical cations, as well as those of other related radical cations, have been determined by MO calculations and correlated with the ESR spectral data. The single- crystal X-ray structures of π-donors (9) and (12) are reported. The most remarkable fact of these structures is the transverse intermolecular contacts between interstacked molecules. The external sulfur atoms of (9) play a central role in its transverse structural pattern. Complexes of donors (9) and (10) with tetracyano-p-quinodimethane (TCNQ) and te- trafluorotetracyano-p-quinodimethane (TCNQF 4 ) have been obtained and characterized

Oxidative Radical Cyclization of (.omega.-Iodoalkyl)indoles and Pyrroles. Synthesis of (-)-Monomorine and Three Diastereomers

Abstract: Addition of excess hydrogen peroxide (10 equiv) to a sonicated solution of FeSO 4 :7H 2 O (1 equiv) in DMSO containing the N-(ω-iodoalgyl)indoles 4, 5, 11, and 13 effected oxidative radical cyclization to 6, 7, 14, and 15, respectively. The (ω-iodoalkyl)pyrroles 21, 22, 27, 38, and 49 underwent analogous cyclization reactions to 23, 24, 28, 39, and 50, respectively. The regiochemistry of these radical cyclization reactions was correctly predicted by FMO calculations in all cases but one. For compound 38, FMO calculations indicated that radical attack should take place at both C-3 and C-5. Only the product of cyclization at C-5, i.e., 39, was observed. The enantiomerically pure bicyclic ketone 42, prepared by the above technique from the iodide 53, was converted into 55 which, on catalytic reduction (H 2 /Rh-Al 2 O 3 ), gave a mixture of (―)-monomorine (40) and three of its diastereoisomers 56-58

Intramolecular [4+2] Cycloaddition Reactions of Conjugated Enynes

Abstract: The intramolecular [4+2] cycloaddition of conjugated enynes provides an efficient and general route to aromatic and dihydroaromatic compounds

Nucleic‐Acid Analogues with Restricted Conformational Flexibility in the Sugar‐Phosphate Backbone (‘bicyclo‐DNA’). Part 3. Synthesis, pairing properties, and calorimetric determination of duplex and triplex stability of decanucleotides from [(3′S,5′R)‐2′‐deoxy‐3′,5′‐ ethano‐β ‐D‐ribofuranosyl]adenine and ‐thymine

Abstract: The synthesis of a new type of oligonucleotide (‘bicyclooligodeoxynucleotide’ = bcd(Xn)) displaying less conformational flexibility in its sugar-phosphate backbone is described, and a characterization of the pairing properties and energetics of the decamers bcd(T10) and bcd (A10) with each other and with complementary RNA and DNA sequences by UV-spectroscopic and calorimetric techniques is given. The results can be summarized as follows: (i) bcd(T10) pairs less strongly to complementary RNA and DNA, whereas bcd(A10) forms stronger duplexes relative to the natural system. (ii) bcd(A10) discriminates between a complementary oligodeoxynucleotide with a mismatch in the center in the same way as d(A10), indicating equal base-pairing selectivity. (iii) bcd(A10) forms more stable triplexes with d(T10) of the pyrimidine-purine-pyrimidine (py · pu · py) motif than d(A10). (iv) The stability of duplexes containing a bicyclic strand is more sensitive towards salt concentration. The higher sensitivity in bcd(A10) containing duplexes is due to a higher differential cation uptake. (v) Differential scanning calorimetric (DSC) analysis of duplex-formation enthalpies shows ΔHvH in all duplexes containing bicyclooligonucleotides to be more negative than ΔHcal, which is compatible with the formation of catenated structures. (vi) Isothermal titration calorimetry (ITC) provides a complete set of thermodynamic data including duplex and triplex association constants for the systems d(A10)/d(T10), bcd(A10)/d(T10), d(A10)/bcd(T10), bcd(A10)/bcd(T10). (vii) All duplexes containing bicyclic strands show a (numerically) reduced pairing entropy term with respect to that of the natural system. (viii) Enthalpies from DSC and ITC are similar, suggesting that the enthalpic contribution from ordered single strands to the overall duplex-formation enthalpy plays a minor role in the duplexes investigated.

Bicyclic hydantoins with a bridgehead nitrogen. Comparison of anticonvulsant activities with binding to the neuronal voltage-dependent sodium channel.

Abstract: The anticonvulsant activity of diphenylhydantoin (DPH or phenytoin) is consistent with its actions on the neuronal voltage-dependent sodium channel. To further elucidate the binding requirements for this site, we synthesized several hydantoin analogs and evaluated these in in vitro sodium channel-binding and/or in vivo whole animal anticonvulsant assays. 5-Pentyl-5-phenylhydantoin (8), the most potent binder to the sodium channel in this study, had the same affinity as DPH (IC50 = 40 microM), revealing that one phenyl ring is sufficient for good interactions. Since our previous studies with monophenyl-substituted bicyclic 2,4-oxazolidinediones suggested that N3-alkylation and the conformational constraint of a 5-alkyl substituent over one face of the oxazolidinedione ring improved activity, we synthesized two examples of analogous bicyclic hydantoins. However, the bicyclic hydantoins were much less potent binders to the neuronal voltage-dependent sodium channel than their monocyclic counterparts. The binding activity for the more potent bicyclic hydantoin, 1,8-diaza-9,10-dioxo-7-phenylbicyclo[5.2.1]decane (4) (IC50 = 427 microM), was comparable to that of the ring-opened, N3-methylated monocyclic hydantoin model, 5-butyl-3-methyl-5-phenylhydantoin (9) (IC50 = 285 microM), and these were 8-11 times less potent than the monocyclic model 8, which contains a free imide NH. Furthermore, 5-butyl-5-phenylhydantoin (7; IC50 = 103 microM) was less potent than 8, suggesting that increased log P may enhance binding. Thus, unlike 2,4-oxazolidinediones, N3-alkylation of hydantoins dramatically decreases sodium channel-binding activity. Bicyclic hydantoin 4 was nevertheless a good anti-MES anticonvulsant in mice (ED50 = 86 mg/kg), although this activity likely results from mechanisms other than interactions at the neuronal voltage-dependent sodium channel. Compound 4 was also relatively neurotoxic (TD50 = 124 mg/kg). These results suggest that the binding of hydantoins to the sodium channel may be enhanced by (a) a free imide NH group and (b) an increased log P. Furthermore, 2,4-oxazolidinediones and hydantoins must either orient differently in the same binding site or interact with different sites on the neuronal voltage-dependent sodium channel.

1-Aza-1,3-bis(triphenylphosphoranylidene)propane: A Novel :CHCH2N: Synthon

Abstract: 1-Aza-1,3-bis(triphenylphosphoranylidene)propane (3), prepared in situ by the reaction of 1-[[(tri-phenylphosphoranylidene)amino]methyl]ben- zotriazole (betmip, 4) with methylidenetriphenylphosphorane followed by treatment with butyllithium, enables convenient preparations of 3H- 2-benzazepine (7), 2,3-diarylpyrroles (8), and primary allylamines (12) and (13)

Cyclic GMP phosphodiesterase inhibitors. 2. Requirement of 6-substitution of quinazoline derivatives for potent and selective inhibitory activity.

Abstract: We synthesized various 4-[[3,4-(methylenedioxy)benzyl]amino]quinazolines substituted at the 5- to 8-positions and evaluated their inhibitory activities toward cyclic GMP phosphodiesterase (cGMP-PDE) from porcine aorta. Monosubstitution at the 6-position was essential for the inhibitory activity, and the preferred substituents were compact and hydrophobic: methoxy (3b, IC50 = 0.23 microM), methyl (3c, 0.10 microM), chloro (3d, 0.019 microM), thiomethyl (3f, 0.031 microM), and cyano (3p, 0.090 microM) groups. Compounds 3b-d,f,p lacked inhibitory activity toward other PDE isozymes (all IC50 values > 100 microM), and their relaxing activities in porcine coronary arteries were well correlated with the inhibitory activities toward cGMP-PDE (r = 0.88, p < 0.05). One of these compounds, 3b, elevated the intracellular cGMP level in isolated porcine coronary arteries without causing any change in the cAMP level. We consider that this series of compounds dilates coronary arteries via potent and specific inhibition of cGMP-PDE.

Conformationally locked nucleoside analogues. Synthesis of dideoxycarbocyclic nucleoside analogues structurally related to neplanocin C

Abstract: The glycon moiety of nucleosides in solution is known to exist in a rapid dynamic equilibrium between extreme northern and southern conformations as defined by the pseudorotation cycle. The concept of preparing rigid nucleoside analogues with the glycon conformation locked in one of these two extremes was tested with the synthesis of some cyclopropane-fused dideoxycarbocyclic nucleosides, similar to the well-known class of anti-HIV active dideoxynucleosides. The new compounds described here are dideoxynucleoside analogues of the fermentation product neplanocin C (6) which exhibits a typical northern geometry for its 6-oxabicyclo[3.1.0]hexane pseudosugar moiety. However, in view of the lability of the epoxide ring in this system, the equivalent cyclopropane-fused bicyclo[3.1.0]hexane system was used instead to prepare the corresponding dideoxynucleoside analogues bearing all the common bases [(+/-)-9-13]. Due to the well-documented preference of unrestricted bicyclo[3.1.0]hexane systems to exist exclusively in a boat conformation, the resulting nucleosides are structurally locked in a typical northern conformation similar to that of neplanocin C. The locked northern conformation in these nucleosides remained unchanged in solution in the 20-80 degrees C temperature range according to variable temperature 1H NMR studies. For the synthesis of these compounds, racemic trans-1-[(benzyloxy)methyl]-4-hydroxybicyclo[3.1.0]hexane [(+/-)-18] was prepared by a samarium-promoted cyclopropanation reaction with the antecedent cyclopentenol. All of the bases were incorporated under Mitsunobu conditions and converted to the desired final products following a standard methodology. Anti-HIV evaluation revealed that only the adenosine analogue (+/-)-9 possessed enough activity to warrant resolution into its optical antipodes. This was realized by chiral HPLC chromatography to give the individual enantiomers (-)-32 and (+)-33. Adenosine deaminase was used to identify isomer (+)-33 as the enantiomer with the "natural" configuration which was solely responsible for the observed biological activity and toxicity of (+/-)-9. It is possible that the exclusive northern conformation adopted by these nucleosides reduces their substrate affinity for the various activating kinases, except in the case of the adenosine analogue.

The Synthesis and Structure of Encapsulating Ligands: Properties of Bicyclic Hexamines

Abstract: Template syntheses based on tris (ethane-1,2-diamine)cobalt(III) lead to cobalt(III) complexes of cage hexamines of the ' sarcophagine ' type ( sarcophagine = sar = 3,6,10,13,16,19- hexaazabicyclo [6.6.6] icosane ) rapidly and in high yield. Reduction of these species to their cobalt(II) forms enables the ligands to be removed in concentrated acids at elevated temperatures, and in hot aqueous solutions containing excess cyanide ion. The free sarcophagine and 1,8-diaminosarcophagine [(NH2)2sar or diamsar] ligands are strong bases, accepting up to four and five protons, respectively, in aqueous solution. In chloride medium, I = 1.0, at 298 K, pK1 = 11.95, pK2 = 10.33, pK3 = 7.17, pK4 ≈ 0 for sarcophagine , and pK1 = 11.44, pK2 = 9.64, pK3 = 6.49, pK4 = 5.48, pK5 ≈ 0 for diaminosarcophagine , with very similar values being found for triflate medium. Crystal structure determinations for both free bases, the chloride, sulfate, perchlorate and nitrate salts of diamsar , the complex of zinc chloride with sar, and the magnesium nitrate complex with diamsar show remarkably small variations in the cavity defined by the bicyclic ligands, though relatively subtle bond length and bond angle changes can be rationalized in terms of the effects of proton and metal ion binding. Exhaustive methylation of sarcophagine produces the highly lipophilic, hexatertiary base hexamethylsarcophagine , which, in the solid state, adopts quite different conformations and nitrogen-atom configurations to those of sar itself. All the ligands rapidly form metal ion complexes of generally exceptional kinetic and thermodynamic stability.