Antagonists of substance P from emphasis on position 11

Ten analogs of substance P (SP) were designed and synthesized. The agonist and antagonist activities against SP were assayed on the isolated guinea pig ileum. The prime designs were changes of the important Met11 to include Leu11, Thr11, D-Leu11 and D-Ala11. Step-wise designs of changing D-Arg1 and D-Pro2 to the corresponding L-configurations resulted in decreasing antagonist activity. Changing Leu11 to D-Leu11 and D-Ala11 reduced antagonist activity. [D-Arg1,D-Pro2,D-Trp7,D-Trp9,Leu11]-SP is the most potent antagonist of this group of analogs, and required a 100-fold increase in the concentration of SP to give 50% of the maximal response caused by SP.     

Design and synthesis of effective antagonists of substance P

The agonist/antagonist activities of four background analogs of substance P (SP) facilitated design and synthesis of 12 new analogs to achieve effective antagonists. (D-Pro2, D-Phe7, D-Trp9)-SP, (D-Pro2, D-Trp7,9)-SP and (D-Arg1, D-Phe7, D-Trp9)-SP showed no agonist activity; 9 analogs showed weak agonist activity of SP. (D-Pro2, D-Trp7,9)-SP was the most potent antagonist which at a concentration of 10(-5) required a 3-fold increase in SP to allow a 50% response by SP. (D-Pro2, Lys6, D-Phe7)-SP and (D-Pro2, D-pClPhe7, D-Trp9)-SP were also potent, and the antagonism was competitive. For specific pairs of peptides, Lys6 is a promising substituent. D-Trp7,9 was as effective as Lys6, D-Phe7. D-pClPhe7 was three times as effective as D-Phe7. D-Dln6 was 1.33-fold better than D-Gln5. D-Pro2 and D-Pro4 were equally effective. D-Pro2 was 1.5 times as effective as D-Lys3. D-Pro2 may not be important. D-pClPhe9 and D-Trp9 were equally effective.     

A new nonpeptide tachykinin NK1 receptor antagonist isolated from the plants of Compositae

To find new tachykinin NK1 receptor antagonists from natural sources, we examined the tachykinin antagonist activity in the extracts of approximately 200 species of plants by the use of isolated guinea pig ileum. As a result, we discovered a novel and potent NK1 receptor antagonist in the extract of dried flowers of Matricaria chamomilla L. (chamomile). The structure of the antagonist was established as N1,N5,N10,N14-tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]-1,5,10,14-tetraazatetradecane (tetracoumaroyl spermine, 1a). The Ki values of 1a, estimated from the inhibitory action on the substance P (SP)-induced contraction of the guinea pig ileum and the inhibition of the binding of [3H][Sar9, Met(O2)11]SP to human NK1 receptors, were 21.9 nM and 3.3 nM, respectively. 1a is the first potent NK1 receptor antagonist from natural sources and it has a unique structure of a polyacylated spermine. 1a was concentrated in pollen of Matricaria chamomilla L. and was also found in the extracts of flowers of other four species of Compositae. In addition, we found N1,N5,N10-tris[3-(4-hydroxyphenyl)-2-propenoyl]-1,5,10,14-tetraazatetradecane (2) as a new compound in the extract of flowers of Matricaria chamomilla L., which did not exhibit any tachykinin antagonist activity. A number of related compounds were synthesized, and the structure-activity relationship was studied.     

Synthesis of substance P analogs and agonistic and antagonistic activities.

Fourteen analogs of substances P (SP), six previously synthesized by a solution method and eight newly synthesized by a solid-phase technique, have been tested for agonistic and antagonistic activities utilizing the isolated guinea pig ileum. The primary objective is to achieve effective inhibitors of SP. These analogs had agonistic activities ranging from negligible to that equivalent to SP. Six of the fourteen analogs had some degree of antagonistic activity [D-Leu8, D-Phe9]-SP is an analog which constitutes a lead to new substitutions, because it had antagonistic activity, but only negligible agonistic activity. One concept for effective antagonistic activity requires negligible or no agonistic activity.     

An extended planar C5 conformation and a 310-helical structure of peptide foldamer composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids

Optically active peptide foldamers Tfa-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (10) and Tfa-[(S)-(alphaEt)Val]-[(S)-(alphaEt)Leu]-[(S)-(alphaEt)Nva]-Deg-[(S)-(alphaEt)Nle]-OEt (11) composed of diverse alpha-ethylated alpha,alpha-disubstituted alpha-amino acids were synthesized. The dominant conformation of these peptides in solution was an unusual, fully extended planar conformation, and that in the crystal state was both right-handed (P) and left-handed (M) 3(10)-helical structures in 10 and a P 3(10)-helical structure in 11, respectively. The preferred planar C(5) conformation of the peptides prepared from chiral alpha-ethylated alpha,alpha-disubstituted alpha-amino acids was drastically different from the 3(10)-helical structure of the peptides prepared from chiral alpha-methylated alpha,alpha-disubstituted alpha-amino acids.     

Agonistic and antagonistic activities of neuromedin U-8 analogs substituted with glycine or D-amino acid on contractile activity of chicken crop smooth muscle preparations.

To study the structure-activity relationships of neuromedin U-8 (NMU-8) (H-Tyr-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2) and to develop a NMU-8 antagonist, twenty-three NMU-8 analogs substituted with Gly or the corresponding D-amino acid(s) at positions 1-8 were synthesized by solid-phase techniques. On isolated chicken crop preparations, the contractile activity of the synthetic NMU-8 analogs was compared with that of NMU-8 and their antagonistic activity was assayed against NMU-8. The replacement of Phe2, Phe4, Arg5, Pro6, Arg7 or Asn8 with Gly brought about a drastic decrease of the agonistic activities. Substitution of the corresponding D-amino acid residue for Phe2, Phe4, Arg5, Pro6 or Asn8 caused a marked decrease of the agonistic activities, while the replacement of Tyr1 with D-form enhanced the activity. It was further revealed that [D-Pro6]-NMU-8 and [D-Leu3, D-Pro6]-NMU-8 exerted a non-competitive antagonistic activity against NMU-8 with x values of 5.22 +/- 0.12 and 5.34 +/- 0.09, respectively. [D-Phe2, D-Pro6]-NMU-8, [D-Arg5, D-Pro6]-NMU-8 and [D-Pro6, D-Asn8]-NMU-8 showed a very weak antagonism. The results indicated that 1) the side chain of each amino acid at positions 2, 4, 5, 6, 7 and 8 of NMU-8 is of relative importance for the expression of the contractile activity, and 2) [D-Pro6]-NMU-8 and its four analogs acted as an antagonist against NMU-8.     

Stable exo-nido-metallacarboranes (M = Os(IV)) that incorporate meta-carborane-based dicarbollide ligands

Reactions of the [K]+ salts of the [nido-7,9-C2B9H12]- anion (2) and its C-phenylated derivative [7-Ph-nido-7,9-C2B9H11]- (4) with [OsCl2(PPh3)3] (3) proceed in benzene at ambient temperature with the formation of 16-electron chlorohydrido-Os(IV) exo-nido complexes, [exo-nido-10,11-{(Ph3P)2OsHCl}-10,11-(mu-H)2-7-R-7,9-C2B9H8] (5: R = H; 6: R = Ph), along with the small amounts of the charge-compensated nido-carboranes [nido-7,9-C2B9H11PPh3] (7) and [7-Ph-nido-7,9-C2B9H10PPh3] (8) as byproducts. However, when carried out under mild heating in ethanol, the reaction of 2 with 3 selectively afforded a 16-electron dihydrido-Os(IV) exo-nido complex [exo-nido-10,11-{(Ph3P)2OsH2}-10,11-(mu-H)2-7,9-C2B9H9] (9). Structures of both complexes 5 and 9 have been confirmed by single-crystal X-ray diffraction studies, which revealed that nido-carboranes in these species function as a bidentate dicarbollide ligands [7-R-nido-7,9-C2B9H10]2- linked to the Os(IV) center via two B-H...Os bonds involving adjacent B-H vertices in the upper CBCBB belt of the carborane cage. Thus, compounds 5 and 9 represent the first structurally characterized exo-nido-metallacarboranes based on meta-dicarbollide-type ligands. Variable-temperature 1H and 31P{1H} NMR experiments indicate that complex 9 is fluxional in solution and shows an unusual exchange between terminal Os-(H)2 and bridging {B-H}2...Os hydrogen atoms. Upon heating in d8-THF at 65 degrees C, complex 9 converts irreversibly to its closo isomer [2,2-(PPh3)2-2,2-H2-closo-2,1,7-OsC2B9H11] (13), which could thus be obtained as a pure crystalline solid. The structure of 13 has been established on the basis of analytical and multinuclear NMR data and a single-crystal X-ray diffraction study.     

Synthesis of 1-(2-Carboxyethylbenzyl)-2-benzenesulfonamidobicyclo[2.2.1]heptane: A Novel Potent Thromboxane Antagonist

A potent thromboxane antagonist, 1-[2-(2-carboxyethyl)benzyl)]-2-benzenesulfonamidobicyclo-[2.2.1]heptane was synthesized from norcamphor in 8 steps. It was shown to be a very potent thromboxane antagonist by inhibition of platelet aggregation induced by U46,619 at nanomolar concentration. The key intermediate 3-[2-bromomethylphenyl]propyl tetrahydropyran ether may be useful for the synthesis of other interphenylene containing prostaglandin analogs.     

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.     

Microwave irradiation： Novel and facile methods for the synthesis of new pyrimidinones

We describe here a rapid process for the preparation of new 9-chloromethyl-12-aryl-10,12-dihydrobenzo[5,6]chromeno[2,3-d]pyrimidin-11-ones 5a-d and 10-chloromethyl-7-aryl-7,9-dihydrobenzo[7,8]chromeno[2,3-d]pyrimidin-8-ones 6a-d by two different methods utilizing microwave irradiation. This methodology provides better yields(72%–80%) and high purity of the title compounds.     

Synthesis of spiro- and dispirotetrahydropyrane-2,4-diones involving cyclobutane fragment in position 5 of heterocycle

Methyl 3-(1-bromocyclobutyl)-2,2-dimethyl-3-oxopropanoates, 1-(1-bromocyclobutyl-carbonyl) cyclopentanoates and 1-(1-bromocyclobutylcarbonyl)cyclobutanoates react with zinc and aromatic aldehydes to form 5-aryl-8,8-dimethyl-6-oxaspiro[3.5]nonane-7,9-diones, 13-aryl-12-oxadispiro[3.1.4.3]tridecane-5,11-diones and 12-aryl-11-oxadispiro[3.1.3.3]dodecane-5,10-diones respectively.     

Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives

A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity, 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2- oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 micrograms/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a] pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED50 11 micrograms/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.     

Reaction of substituted chalcones with methyl 1-bromocycloalkanecarboxylates and zinc

Methyl 1-bromocyclopentane-and 1-bromocyclobutanecarboxylates react with zinc and substituted chalcones to form spiro-3,4-dihydropyran-2-one derivatives: 8, 10-diaryl-7-oxaspiro[4.5]dec-8-en-6-ones and 7,9-diaryl-6-oxaspiro[3.5]non-7-en-5-ones, respectively.     

Non-glutamate type pyrrolo[2,3-d]pyrimidine antifolates. III. Synthesis and biological properties of N(omega)-masked ornithine analogs

The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-g lutamic acid (1b, TNP-351) and the related compound (1a), was replaced with various N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-2,omega-diaminoalkanoic acids, and the inhibitory effects of the resulting products (9, 11, 14, 18, 21, 23, 25, 30, 36) on dihydrofolate reductase (DHFR), the growth of murine fibrosarcoma Meth A cells, and methotrexate-resistant human CCRF-CEM cells, were examined. Compounds (9a-f) acylated with a hemiphthaloyl group were efficiently synthesized by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (7a,b) and N(omega)-phthaloyl 2,omega-diaminoalkanoic acid methyl esters (6a-c) and subsequent hydrolysis. The other N(omega)-acyl- and sulfonyl-ornithine analogs (21, 23, 25) were synthesized by acylation of free amino intermediates (19a,b) derived from tert-butoxycarbonyl-ornithine analogs (17a,b). A free ornithine analog (18) did not strongly inhibit Meth A cell growth, whereas all N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-ornithine analogs (9, 11, 21, 23, 25, 30, 36) exhibited much more potent inhibitory activities against both DHFR and Meth A cell growth. In particular, compounds 9c, 21k and 36a also showed remarkable growth-inhibitory activities against methotrexate-resistant CCRF-CEM cells. These results demonstrate that the potent inhibitory activities of N(omega)-masked ornithine analogs against the growth of Meth A cells and methotrexate-resistant CCRF-CEM cells, results from effective uptake via reduced folate carrier and their potent DHFR inhibition.     

The synthesis of ventiloquinone L, the monomer of cardinalin 3

Readily available ethyl-4-acetoxy-6,8-dimethoxynaphthalene-2-carboxylate was converted into 1-[3-allyl-4-(benzyloxy)-6,8-dimethoxy-2-naphthyl)-1-ethanol in seven steps. Subjection of this compound to Wacker oxidation conditions provided 5-benzyloxy-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochromene in good yield. Hydrogenation of the isochromene afforded (+/-)-cis-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochroman-5-ol as the major product, which was readily converted into ventiloquinone L.     

Structure-activity relationships of alpha-human atrial natriuretic peptide (alpha-hANP) analogs: role of charged groups in alpha-hANP.

To determine whether the addition of a methylene unit in the side chain of the Asp or Arg residue in alpha-human atrial natriuretic peptide (alpha-hANP) influences its biological activity, analogs of alpha-hANP, [Glu13]-alpha-hANP (7-28) (1), [Aad13]-alpha-hANP (7-28) (2), and [Harn]-alpha-hANP(7-28) (where n is any possible combination of 11, 14 and 27) (3-9), where the original Asp or Arg residue was replaced by a homo-amino acid, were synthesized by the solid-phase synthesis method. All the analogs were evaluated for their receptor binding, cyclic guanosine monophosphate (cGMP) accumulation activity in rat vascular smooth muscle cells (VSMC), and for vasorelaxant activity employing rat aorta. 1 and 2 were 0.9 and 0.03 times as potent as alpha-hANP (7-28), respectively, in binding. Har-containing analogs (3-9) were as potent as alpha-hANP (7-28) in binding. Among the Har-containing analogs, [Har11,14]-alpha-hANP (7-28) (6) and [Har11,27]-alpha-hANP (7-28) (7) were remarkably vasorelaxant active, being 4.2 and 5.3 times potent than alpha-hANP (7-28), respectively, in spite of relatively lower cGMP accumulation activity in the case of 7. The roles of the chargeable amino acid residues in biological activity are discussed.     

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.     

meso-四(2-羟基-5-磺酸苯基)卟啉的合成及其酸碱平衡的研究

本文对 meso-四(2-H-5-SP)P 的提纯方法进行了改进,同时以光度法研究了该试剂在水溶液中的酸碱平衡、测得其 pKa_1、pKa_2、pKa_3、pKa_4分别为2.99,4.21,8.68,10.28。     

Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo[3,2-c]azepines and related compounds

A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl- 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak alpha1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.     

Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins

The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM), and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.