Analogues of a potent oxytocin antagonist with truncated C-terminus or shorter amino acid side chain of the basic amino acid at position 8.

Twelve analogues were synthesized, their structure derived from modifications of [(S)Pmp1, D-Trp2, Pen6, Arg8]oxytocin, PA, in which (S)Pmp = beta,beta-(3-thiapentamethylene-beta-mercaptopropionic acid). PA is a potent antagonist of the uterotonic effect of oxytocin in the rat (uterotonic test in vitro, pA2 = 8.86) and in the baboon. Truncated analogues of PA from the C-terminus were systematically prepared ending in either the free acid or the amide, i.e. PA1-9 acid, PA1-8 acid, PA1-7 acid, PA1-6 acid, PA1-8 amide, PA1-7 amide and PA1-6 amide. PA1-8 amide was roughly as potent as PA in the rat uterotonic assay in vitro, and the shorter amides were only somewhat weaker antagonists. All four acid analogues were weaker antagonists than PA but still maintained rather high antagonistic potency. These findings suggest that, if these truncated acids form as metabolites in vivo, they may contribute to the overall biological effect of PA and their contribution should be taken into account. Furthermore, using these analogues, the radioimmunoassay measurements of PA may be standardized, as they may cross react with PA antibodies and interfere with the determination. In addition, five analogues were made by substituting Arg8 of PA with Lys, Orn8, Dab8, Dap8 and Cit8. All of these analogues maintained high potency as OTAs in the uterotonic assay, although their activity was only about 1.5-3 times lower than PA. The most potent analogue in the uterotonic assay, [Dap8]PA, pA2 = 8.53, had weak pressor activity (pA2 = 6.90) and no antidiuretic effect. The pressor activity was lower for all tested acids, and for PA1-6 acid it was even below the detection limit. Additionally, PA1-9 acid, PA1-7 acid and PA1-6 acid showed no antidiuretic activity. Hence, the PA1-6 acid is a potent OTA with pA2 = 8.27 and no measurable effect in the pressor or antidiuretic tests and thus it is a pure oxytocin antagonist. This fact makes it an attractive candidate for further studies on inhibition of OT biological effects and on preterm labour.     

Substance P analogs containing alpha,alpha-dialkylated amino acids with potent anticancer activity.

Six analogs (peptides 1-6) of the potent substance P (SP) derivative known as 'Antagonist D' were synthesized by substituting constrained amino acids Aib or Acp (cycloleucine, 1-amino cyclopentane carboxylic acid) at different positions in the Antagonist D sequence: D-Arg(1)-Pro(2)-Lys(3)-Pro(4)-D-Phe(5)-Gln(6)-D-Trp(7)-Phe(8)-D-Trp(9)-Leu(10)-Leu(11)-NH(2). In the preliminary in vitro antiproliferative screening of the analogs on different human cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, peptide 1 was found to be the most active. Further, peptide 1 was butanoylated (analog 5) or octanoylated (analog 6) at the N-terminus. SP analogs 1, 5, and 6 were evaluated in vivo in a xenograft model of human primary colon tumor (PTC) cell line in athymic nude mice and were found to cause tumor regression. This study investigates if the use of the constrained amino acids Aib and Acp in the designed SP analogs can retain the in vitro and in vivo anticancer activities, which could be useful in cancer therapy and drug targeting. Further, the strategy of incorporation of Aib or Acp in biologically active peptides can be exploited in determining the receptor-bound conformation and in transforming these bioactive peptides into pharmacologically useful drugs.     

Analogues of oxytocin antagonists bearing a ureido group in the amino acid side chain at position 4 or 5.

Substitution of the side chain carboxamido group at position 4 in the potent oxytocin antagonist (OTA) [ThiaPmp(1), D-Trp(2), Cys(6), Arg(8)]-OT, PA, in which ThiaPmp = beta,beta-(3-thiapentamethylene)-beta-mercaptopropionic acid, led to [Orn(Car)(4)]-PA, ([Cit(4)]-PA), which had uterotonic antagonistic activity equal to that of PA. The same modification at position 5, leading to [Cit(5)]-PA, resulted in antagonistic potency more than 10 times lower than that of PA. This paper also describes the same substitutions introduced in the highly potent OTA [Pen(6)]-PA (antioxytocic in vitro pA(2) = 8.72). Analogues of the general formula [U(4)-X(5)-Pen(6)]-PA, in which U = Lys, Orn, Dab, Dap or X = Orn, Dab or Dap, were synthesized by SPPS. Each of these analogues was carbamoylated by treatment with KCNO in DMF-H(2)O, yielding the corresponding U(Car)(4) or X(Car)(5) derivatives. In the uterotonic assay, the substitution with the ureido group at Gln(4) results in retention of high antagonistic potency, albeit somewhat lower than that of PA, e.g. [Orn(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA having pA(2) = 8.52 and pA(2) = 8.42 respectively. In the pressor assay, [Lys(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA were somewhat weaker antagonists of arginine vasopressin than [Pen(6)]-PA; [Dap(Car)(4), Pen(6)]-PA showed only a faint trace of pressor agonistic activity. The substitution with the ureido group at position 5 leads to a significant loss of OTA potency in the in vitro uterotonic assay. The [Orn(Car)(5), Pen(6)]-PA was the most potent of the series (pA(2) = 8.05). An interesting finding is that [Dap(Car)(5), Pen(6)]-PA is equipotent with its precursor [Dap(5), Pen(6)]-PA (potency in the uterotonic test in vitro, pA(2) = 7.71 and pA(2) = 7.68, respectively). Furthermore, neither [Dap(5), Pen(6)]-PA nor [Dap(5), Pen(6), Gly(9)]-PA exhibited activity in the antidiuretic or pressor assays. Although these last two analogues show some decrease in antioxytocin potency, they behave as pure oxytocin antagonists, which makes them attractive candidates for further studies on the development of potent and specific OTAs.     

Beta 2-agonist treatment enhances uterine oxytocin receptor mRNA expression in pregnant rats

The objective of this study was to disclose an interaction between Beta(2)-adrenergic (Beta(2)-ARs) and oxytocin (OT) receptors (OTRs) in the late-pregnant rat uterus. We investigated the level of uterine OTR mRNA expression after the administration of Beta(2)-AR agonists fenoterol and hexoprenaline to rats from day 18 to 22 of pregnancy, and also tested the effect of fenoterol on uterine explants. Hexoprenaline induced a maximum 24% increase of OTR mRNA. Fenoterol in vivo elicited a maximum 125% increase of OTR mRNA, in vitro produced a maximum fourfold increase in OTR mRNA. In fenoterol-treated rats the maximal contractility increasing effect of OT on isolated uterine rings was significantly higher than in intact term pregnant rats, but the EC50 values were not statistically different. It was concluded that the enhanced expression of OTR mRNA induced by Beta(2)-agonists in the late-pregnant rat uterus may be a possible drawback to effective therapy of preterm uterine contractions with Beta(2)-agonists.     

Steroidal constituents of rice (Rryza sativa) hulls with algicidal and herbicidal activity against blue-green algae and duckweed

Two new compounds, 14-methyl stigmast-9(11)-en-3alpha-ol-3beta-D-glucopyranoside (1) and cholest-11-en-3beta, 6beta, 7alpha, 22beta-tetraol-24-one-3beta-palmitoleate (2), along with the known compound beta-sitosteryl-3beta-D-glucopyranosyl-6'-linoleiate (3), were isolated from the methanolic extract of rice (Oryza sativa) hulls. The structures of the two new compounds were elucidated using one- and two-dimensional NMR in combination with IR, EI/MS, FAB/MS, HR-EI/MS and HR-FAB/MS. In bioassays with blue-green algae, Microcystis aeruginosa UTEX 2388 and duckweed, Lemna paucicostata Hegelm 381, the efficacy of bioactivity of the two new compounds linearly increased as the concentration increased from 0.3 to 300 IgM. Compared with momilactone A, compounds 1 and 2 showed similar and higher inhibitory activities against the growth of M. aeruginosa at a concentration of 300 microM. However, compound 2 was similar to momilactone A in inhibiting L. paucicostata growth at a concentration of 300 microM. As a result, compound 2 appears to have a strong potential for the environmentally friendly control of weed and algae that are harmful to water-logged rice.     

Synthesis of tetrazole analogs of gamma- and delta-amino acids.

N-benzyloxycarbonyl-protected alpha- or beta-amino alcohols, easily prepared from alpha- and beta-amino acids, were converted into aldehydes and directly reacted with (triphenyl phosphoranylidene) acetonitrile, leading to unsaturated nitriles. Treatment of nitriles with NaN(3) and ZnBr(2) produced unsaturated gamma- and delta-amino tetrazoles, which were deprotected and converted to the corresponding saturated compounds by catalytic hydrogenation. For the case of delta-amino tetrazole, the methylation of the acidic moiety occurred after treatment with CH(2)N(2), leading to the N(1)- and N(2)-methylated constitutional isomers, which were separated by column chromatography and hydrogenated.     

Chirality transferring [3,3] sigmatropic rearrangement of (1-Acyloxy-2-alkenyl)trianlkylsilane synthesis of optically active vinylsilane-containing alpha-amino acid

A vinylsilane-containing alpha-amino acid and alpha,alpha-disubstituted alpha-amino acid 2 having two contiguous asymmetric carbon centers at their alpha and beta positions were synthesized in an optically active form by ester-enolate Claisen rearrangement of the alpha-acyloxysilane 1 as the key step, where the chirality of an alpha-acyloxy-TBDMS group was completely transferred to the rearranged product.     

Unique reactivity of alpha,beta-unsaturated carboxylic acid imidazolides: catalytic asymmetric synthesis of alpha,beta-epoxy esters and alpha,beta-epoxy carboxylic acid derivatives

Catalytic asymmetric synthesis of alpha,beta-epoxy esters and alpha,beta-epoxy carboxylic acid derivatives is described. Catalytic asymmetric epoxidation of alpha,beta-unsaturated carboxylic acid imidazolides using La-BINOL-Ph(3)As=O complex gave the corresponding alpha,beta-epoxy peroxy tert-butyl esters, which were directly converted to the alpha,beta-epoxy methyl esters by adding methanol to the reaction. This catalytic system had broad generality for epoxidation of various substrates. With the use of 5-10 mol% of the catalyst, both beta-aryl and beta-alkyl-substituted-alpha,beta-epoxy methyl esters were obtained in up to 91% yield and in up to 93% enantiomeric excess. In addition, efficient transformations of alpha,beta-epoxy peroxy tert-butyl esters into the alpha,beta-epoxy amides, alpha,beta-epoxy aldehydes, and gamma,delta-epoxy beta-keto esters are also reported.     

Crystal-state conformation of Calpha,alpha-dialkylated peptides containing chiral beta-homo-residues.

Secondary structure formation and stability are essential features in the knowledge of complex folding topology of biomolecules. To better understand the relationships between preferred conformations and functional properties of beta-homo-amino acids, the synthesis and conformational characterization by X-ray diffraction analysis of peptides containing conformationally constrained Calpha,alpha-dialkylated amino acid residues, such as alpha-aminoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single beta-homoamino acid, differently displaced along the peptide sequence have been carried out. The peptides investigated are: Boc-betaHLeu-(Ac6c)2-OMe, Boc-Ac6c-betaHLeu-(Ac6c)2-OMe and Boc-betaHVal-(Aib)5-OtBu, together with the C-protected beta-homo-residue HCl.H-betaHVal-OMe. The results indicate that the insertion of a betaH-residue at position 1 or 2 of peptides containing strong helix-inducing, bulky Calpha,alpha-disubstituted amino acid residues does not induce any specific conformational preferences. In the crystal state, most of the NH groups of beta-homo residues of tri- and tetrapeptides are not involved in intramolecular hydrogen bonds, thus failing to achieve helical structures similar to those of peptides exclusively constituted of Calpha,alpha-disubstituted amino acid residues. However, by repeating the structural motifs observed in the molecules investigated, a beta-pleated sheet secondary structure, and a new helical structure, named (14/15)-helix, were generated, corresponding to calculated minimum-energy conformations. Our findings, as well as literature data, strongly indicate that conformations of betaH-residues, with the micro torsion angle equal to -60 degrees, are very unlikely.     

Endothelial cell and macrophage regulation of vascular smooth muscle cell calcification modulated by cholestane-3beta, 5alpha, 6beta-triol

The cellular and molecular mechanisms that mediate vascular calcification remain poorly understood. In our previous study, oxysterol cholestane-3beta, 5alpha, 6beta-triol (Triol) was shown to promote vascular smooth muscle cells (VSMCs) calcification. In this study, by using direct coculture, non-contact transwell coculture, and culture with conditioned media, we investigated the roles of endothelial cells (ECs) and macrophages in the regulation of VSMCs calcification in the absence or presence of Triol. In vitro calcification was induced by incubation of VSMCs with beta-glycerophosphate. The results showed that ECs inhibited VSMCs calcification, as manifested by the reduction of calcium deposition in extracellular matrix. This effect of ECs on calcification was via the secreted soluble factors. Furthermore, the stimulation of ECs by Triol had no influence on ECs inhibition of calcification. On the other hand, macrophages promoted VSMCs calcification via the secreted soluble factors such as reactive oxygen species, which was further enhanced by Triol. Our results supported the roles for ECs and macrophages in vascular calcification, modulated by oxysterols in atherosclerotic plaque.     

Bradykinin analogs containing the 4-amino-2-benzazepin-3-one scaffold at the C-terminus.

High affinity peptide ligands for the bradykinin (BK) B(2) subtype receptor have been shown to adopt a beta-turn conformation of the C-terminal tetrapeptide (H-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)-OH). We investigated the replacement of the Pro(7)-Phe(8) dipeptide moiety in BK or the D-Tic(7)-Oic(8) subunit in HOE140 (H-D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-Oic(8)-Arg(9)-OH) by 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one templates (Aba). Binding studies to the human B(2) receptor showed a correlation between the affinities of the BK analogs and the propensity of the templates to adopt a beta-turn conformation. The L-spiro-Aba-Gly containing HOE140 analog BK10 has the best affinity, which correlates with the known turn-inducing property of this template. All the compounds did not modify basal inositolphosphate (IP) output in B(2)-expressing CHO cells up to 10 microM concentration. The antagonist properties were confirmed by the guinea pig ileum smooth muscle contractility assay. The new amino-benzazepinone (Aba) substituted BK analogs were found to be surmountable antagonists.     

Synthetic formyl tripeptide chemoattractants: a C(alpha,alpha)-dialkylated, amphiphilic glycyl residue at position 1.

The two diastereomeric tripeptides f-(S)-HmMet-Leu-Phe-OMe and f-(R)-HmMet-Leu-Phe-OMe, analogues of the prototypical chemoattractant f-Met-Leu-Phe-OH, were synthesized in solution by classical methods and fully characterized. A conformational study was performed in solution by 1H-NMR. Concomitantly, the two peptides were tested for their ability to induce chemotaxis, superoxide anion production and lysozyme secretion from human neutrophils. The conformational and biological data are discussed with regard to the proposed model of the chemotactic receptor on neutrophils.     

A new active vitamin D analog,ED-71, causes increase in bone mass with preferential effects on bone in osteoporotic patients

As a candidate for active vitamin D analogs that have selective effects on bone, 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) has been synthesized and is currently under clinical trials. In ovariectomized rat model for osteoporosis, ED-71 caused an increase bone mass at the lumbar vertebra to a greater extent than 1alpha-hydroxyvitamin D3 (alfacalcidol), while enhancing calcium absorption and decreasing serum parathyroid hormone levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers.An early phase II clinical trial was conducted with 109 primary osteoporotic patients. The results indicate that oral daily administration of ED-71 (0.25, 0.5, 0.75, and 1.0 microgram) for 6 months increased lumbar bone mineral density in a dose-dependent manner without causing hypercalcemia and hypercalciuria. ED-71 also exhibited a dose-dependent suppression of urinary deoxypyridinoline with no significant reduction in serum osteocalcin. These results demonstrate that ED-71 has preferential effects on bone with diminished effects on intestinal calcium absorption. ED-71 offers potentially a new modality of therapy for osteoporosis with selective effects on bone.     

Immunohistochemical detection of the retinoid acid receptors (RXR-alpha, -beta, -gamma) and Farnesoid X-activated receptor (FXR) in the marbled newt along the annual cycle

Retinoid acid receptors (RXR-alpha, -beta, -gamma) and Farnesoid X-activated receptor (FXR) expression in the testis of the marbled newt were investigated with special attention to the changes during the annual testicular cycle, using light microscopy immunohistochemistry and Western blot analysis. The annual testicular cycle of the marbled newt (Triturus marmoratus marmoratus) comprises three periods: (a) proliferative period (germ cell proliferation from primordial germ cells to round spermatids, April-June); (b) spermiogenesis period (July-September); and (c) quiescence period (interstitial and follicular cells form the glandular tissue, October-April). In the proliferative period, primordial germ cells and primary spermatogonia immunostained intensely to the three types of RXRs and also to FXR. In the other periods, immunostaining to these antibodies was weak or absent. Secondary spermatogonia stained weakly to the four antibodies in the proliferative period, and only to FXR, also weakly, in the spermiogenesis period. Immunoreactive primary spermatocytes were weakly labeled with the RXR antibodies in the proliferative period. Spermatids and spermatozoa did not stain to any antibody in any period. Follicular cells only immunostained to RXR-gamma and only in the quiescence period when they are forming the glandular tissue, together with the interstitial cells. As follicular cells, interstitial cells only immunostained in the quiescence period; however, they immunoreacted to the three types of RXRs. These findings suggest that in the newt, RXRs and FXR are involved in spermatogenesis control by regulating the proliferation of primordial germ cells and spermatogonia. In addition, RXR-gamma seems to be also involved in the development of the glandular (steroidogenic) tissue.     

Studies on intramolecular hydrogen bonding between the pyridine nitrogen and the amide hydrogen of the peptide: synthesis and conformational analysis of tripeptides containing novel amino acids with a pyridine ring.

For the first time tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1) and AA(3) = Gly or Aib, Xaa = 2Pmg and 2Pyg) were prepared containing alpha-methyl-alpha-(2-pyridyl)glycine (2Pmg) and alpha-(2-pyridyl)glycine (2Pyg) by solid-phase Ugi reaction. These results clearly indicate that for the preparation of tripeptides containing an amino acid with a pyridine ring, the solid-phase Ugi reaction is very useful.NMR analysis clarified that 2Pmg-containing tripeptides adopt a unique conformation with an intramolecular hydrogen bond between 2Pmg-NH and the pyridine nitrogen. However, in the case of Z-Gly-2Pyg-Gly-OMe, the intramolecular hydrogen bonding between 2Pyg-NH and the pyridine nitrogen was not observed, whereas Z-Aib-2Pyg-Aib-OMe adopts a unique conformation with an intramolecular hydrogen bond between 2Pyg-NH and a pyridine nitrogen. Conformational analysis of the tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1), AA(3) = Gly or Aib, Xaa = alpha,alpha-di(2-pyridyl)glycine (2Dpy), alpha-phenyl-alpha-(2-pyridyl)glycine (2Ppg), 2Pmg and 2Pyg), clarified that when an alpha,alpha-disubstituted glycine with a 2-pyridyl group at an alpha-carbon atom is introduced into any peptide, an intramolecular hydrogen bond between a pyridine nitrogen and an amide proton is formed and conformational mobility of the peptide backbone is restricted.     

Stereocontrolled synthesis of 1-acetylen-2,3-di-o-benzyl-tetrahydrofurans, 1,4-anhydro-arabinitol,and alpha,beta-dihydroxy-gamma-alkyl-butyrolactones

This article describes a concise and efficient synthesis of 1-acetylen-2,3-di-O-benzyl-tetrahydrofurans from tartaric acid esters using as the key step the stereocontrolled cyclization of Co(2)(CO)(6)-complexed propargylic diols. This molecule led to enantiomerically pure 1,4-anhydro-arabinitol and alpha,beta-dihydroxy-gamma-alkyl-butyrolactones. In the latter case, the critical methylene oxidation at the oxygen vicinal position was performed by RuO(4).     

Fast conventional Fmoc solid-phase peptide synthesis with HCTU.

1H-Benzotriazolium 1-[bis(dimethyl-amino)methylene]-5-chloro-hexafluorophosphate (1-),3-oxide (HCTU) is a nontoxic, nonirritating and noncorrosive coupling reagent. Seven biologically active peptides (GHRP-6, (65-74)ACP, oxytocin, G-LHRH, C-peptide, hAmylin(1-37), and beta-amyloid(1-42)) were synthesized with reaction times reduced to deprotection times of 3 min or less and coupling times of 5 min or less using HCTU as the coupling reagent. Expensive coupling reagents or special techniques were not used. Total peptide synthesis times were dramatically reduced by as much as 42.5 h (1.8 days) without reducing the crude peptide purities. It was shown that HCTU can be used as an affordable, efficient coupling reagent for fast Fmoc solid-phase peptide synthesis.     

Synthesis of glyoxylyl peptides using an Fmoc-protected alpha,alpha'-diaminoacetic acid derivative.

The synthesis of glyoxylyl peptides by coupling the masked glyoxylic acid derivative (FmocNH)(2)CHCO(2)H, 1, to a peptidyl resin assembled using Fmoc/tert-butyl chemistry has been described recently. Deprotection and cleavage of the peptide from the solid support using TFA was followed by unmasking of the glyoxylyl group in solution in the presence of DBU. [] The glyoxylyl peptide was thus generated using non-oxidizing conditions by comparison with the method based on the periodic oxidation of a seryl-precursor. However, base treatment of the (FmocNH)(2)CHCO(2)-peptide led to the formation of a byproduct besides the desired glyoxylyl peptide. This paper describes an optimized procedure for unmasking the Fmoc-protected alpha,alpha'-diaminoacetic acid moiety in solution which suppressed byproduct formation. Also presented is a series of experiments that permitted a structure and a mechanism of formation for the byproduct to be suggested.     

Enzymatic hydrolysis of water-soluble wheat arabinoxylan. 1. Synergy between alpha-L-arabinofuranosidases,endo-1,4-beta-xylanases,and beta-xylosidase activities

Hydrolysis of arabinoxylan is an important prerequisite for improved utilization of wheat hemicellulose in the ethanol fermentation industry. This study investigates the individual and combined efficiencies of three commercial, cellulytic and hemicellulytic enzyme preparations, Celluclast 1.5 L, Ultraflo L, and Viscozyme L, in catalyzing the liberation of arabinose and xylose from water-soluble wheat arabinoxylan. Ultraflo L was the best enzyme preparation for releasing arabinose, liberating 53 wt% of the theoretical maximum after 48 h of reaction (10 wt% enzyme/substrate ratio, 40 degrees C, pH 6). Celluclast 1.5 L was superior to the other enzyme preparations in releasing xylose, liberating 26 wt% of the theoretical maximum after 48 h of reaction (10 wt% enzyme/substrate ratio, 50 degrees C, pH 5). The 50:50 mixtures of the enzyme preparations showed no synergistic cooperation in arabinose release, but a synergistic interaction in xylose release was found between Ultraflo L and Celluclast 1.5 L. On the basis of high-performance anion exchange chromatography (HPAEC) analysis of the hydrolysates after enzymatic reaction, we propose that the observed synergism between Celluclast 1.5 L and Ultraflo L is the result of positive interaction between alpha-L-arabinofuranosidase and endo-1,4-beta-xylanase activities present in Ultraflo L that released arabinose, xylobiose and xylotriose, and beta-xylosidase activities in Celluclast 1.5 L, capable of catalyzing the hydrolysis of xylobiose and xylotriose to xylose.     

Anti-initiating activity of 3beta-methoxy-13alpha,14alpha-epoxyserratan-21beta-ol (PJJ-34) from the stem bark of Picea jezoensis Carr. var. jezoensis

Ultraviolet light is the major cause of skin cancers in human, and several effects of ultraviolet light B (UVB) are thought to contribute to skin photocarcinogenesis. 3Beta-methoxy-13alpha,14alpha-epoxyserratan-21beta-ol (PJJ-34; 1) isolated from Picea jezoensis Carr. var. jezoensis showed the strongest antitumor-promoting activity among naturally occurring triterpenoids in the in vivo two-stage mouse skin-carcinogenesis test. To investigate the anti-initiating activity, we further studied mouse models initiated with ultraviolet-B (UVB) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). Oral administration of the PJJ-34 (1) during a period before and after the three times of UVB irradiation led to a remarkable effect: oral administration of a 0.0025% solution of 1 only to the test group, which started one week before and ended one week after the irradiation, showed less than half papillomas, and inhibition of tumor incidence and tumor multiplicity in comparison to the control group. Therefore, it was recognized that PJJ-34 (1) showed strong anti-initiating activity as well as anti-promoting activity. After all, 1 seems to be useful as cancer-chemopreventive agent.