The sarcodictyins A-F and eleutherobin comprise a family of marine-derived diterpenoids with potent cytotoxicities against various tumor cell lines. Investigations have revealed that several of thess compounds exert their cytotoxic effects through tubulin binding in a mechanism analogous to that of the clinical anticancer drug taxol^TM. The biological importance, challenging molecular architecture, and relative scarcity of these natural products have prompted several groups to undertake their total chemical synthesis. In this review, we summarize the current synthetic efforts and examine the preliminary structure-activity relationships which have emerged from early combinatorial libraries.

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Two new sphingolipids, (2S, 3S, 4R)-1, 3, 4-trihydroxy-2-[((R)-2'-hydroxytetradecanoyl) amino] tricosane (4) and (2S, 3S, 4R)-1, 3, 4-triacetoxy-2-[((R)-2'-acetoxyoctadecanoyl) amino]octadecane (5) along with africanene (1, )reasonably good yield), 23-demethylgargosterol (2) and batylalcohol (3) have been isolated from the soft coral Sinularia leptoclados. Preliminary studies for pharmacological activity (blind screening and toxicity studies) of africanene were conducted. Africanene exhibited in vitro and in vivo cytotoxicity, does dependent hypotensive activity as well as antiinflammatory activity. The pharmacological and toxicity studies on africanene are being reported for the first time and findings strongly encourage further investigation. Compounds 1, 4 and 5 were studied for the antibacterial, antifungal and antiviral activity while compounds 4 and 5 were also studied for the short term in vitro cytotoxic activity.

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A series of quinones (3a-i, 4-9, 11) and aromatic compounds (2a, 2b, 2g) containing the thiophene ring were tested in vitro against the trypomastigote form of Trypanosoma cruzi and the promastigote forms of Leishmania. The quinones 3a-i, 4, 5a, b, 6 and 9 having the thiophene ring fused to a quinone nucleus were the most active members of the series. The electron affinities of the benzo[b]thiophene-4, 7-quinones 3, evaluated by their LUMO energies and halfwave potentials, are reported.

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The synthetic utility of tert-butyl azidoacetate (7) on the Hemetsberger-Knittel reaction is described. The following two findings are disclosed by using tert-butyl azidoacetate (7) : i) in the first step for the synthesis of ethyl indole-2-carboxylate 4, the aldol reaction of less reactive aldehydes 1a, b was improved greatly; ii) tert-butyl indole-2-carboxylate 10 becomes readily available from aldehydes.

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The pharmacological activity of eight pregnane derivatives 17-α acetoxyprogesterone 9, 17-α acetoxy-4, 5-epoxypregnan-3, 20-dione 10, 17-α acetoxy-4-chloro-4-pregnene-3, 20-dione 11, 17-α acetoxy-4-bromo-4-pregnene-3, 20-dione 12, 17-α hydroxy-4-bromo-4-pregnene-3, 20-dione 13, 4-chloro-17-α hydroxy-4-pregnene-3, 20-dione 14, 17-α benzoyloxy-4-bromo-4-pregnene-3, 20-dione 15 and 17-α benzoyloxy-4-chloro-4-pregnene-3, 20-dione 16 was aeter, mined. These compounds were evaluated as antiandrogens on gonadectomized hamster seminal vesicles.The pharmacological data in this study indicate that compounds 15 and 16 having a C-17 benzoyloxy moiety showed the highest antiandrogenic activity as measured by the reduction of the weight of the seminal vesicles, followed by the steroids 11 and 12 (17-α acetoxy group). The free alcohols 13 and 14 exhibited a lower antiandrogenic activity. Apparently, the ester moiety at C-17 is a necessary requirement for the presence of high antiandrogenic activity. shows the inhibitory effect on the conversion of testosterone (T) to DHT, of the above described steroids as measured by the amount of produced DHT 2 expressed as pmoles of DHT/g of protein/h.Steroids 11, 12 and 16 showed a much higher inhibitory activity on the conversion of testosterone (T) to dihydrotestosterone (DHT) than presently used finasteride 3.

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Sialyl Lewis X (1) is known to be a ligand of the cell adhesion molecule E-selectin. We have synthesized several biantennary glycoside-terminated ligands mimicking sialyl Lewis X (1), and evaluated their binding activity to E-selectin using HL-60 cells expressing sialyl Lewis X epitope and human umbilical vein endothelial cells (HU-VECs). These compounds were found to possess moderate binding activities to E-selectin. Among them, di-fucoside analogn (8) which has no sialic acid carboxylate group was more active than 2, which had both the sialyl-galactose residue and the fucose residue (IC₅₀, 8 : 4.7 mM, 2 : 11.7 mM). Furthemore, in the rat pleuritic model in vivo induced by carrageenin, 8 was found to reduce neutrophil infiltration at inflammatory lesions.

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The sec-nitrodienamines 3 were prepared by reaction of the tert-nitrodienamine 1 with primary amines. The reaction of 3 with acetaldehyde afforded 2-methyl-3-nitro-1, 2-dihydropyridines 5, providing a new and efficient heterocyclic annulation reaction.

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To develop a simple chemical deblocking method for Myr-Gly-peptide, we investigated the susceptibility and stability of the internal peptide linkages of model peptides, Myr-Gly-X-Phe-OH (X=Gly, Ala, Val, Lys, His, Arg, Ile, Glu, Gln, Asp, Asn), to HCl, H₂SO₄ and methanesulfonic acid (MSA) at 25 and 60°C, and analyzed the hydrolysates by HPLC. The results indicated that acid hydrolysis in concentrated acids was superior for selective cleavage of the Gly-X linkage. Here, we describe a simple method for regioselective cleavage of the Gly-X bond of Myr-Gly-X-Phe-OH by acids and determination of the decomposition products by RP-HPLC.

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Stereoselective synthesis of 4'-α-alkylcarbovir derivatives 4 was described based on asymmetric synthesis or a chemoenzymatic procedure. The asymmetric alkylation of chiral acetal 7 gave the alkylated enol ethers 9a-c possessing a chiral quaternary carbon. The key carbocyclic intermediates 14a-c were synthesized from 9a-c via eleven-steps. Coupling of 14a-c with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis afforded the target compounds 4a-c in moderate yield. The optically active cyclopentene intermediates 5a-c and 6a-c were also prepared by enzymatic resolution of (±)-5a-c and (±)-6a-c, respectively.

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Two kinds of glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows : the trisaccharide 2-(tetradecyl)hexadecyl α-D-mannopyranosyl-(1→4)-β-D-galactopyranosyl-(1→6)-β-D-galactopyranoside (13) and the tetrasaccharide 2-(tetradecyl) hexadecyl α-D-galactopyranosyl-(1→6)-[α-D-mannopyranosyl-(1→4)]-β-D-galactopyranosyl-(1→6)-β-D-galactpyranoside (20) were synthesized by stepwise condensation of suitably protected monosaccharide units. A 2-(trimethylsilyl)ethyl 2, 3, 4-tri-O-benzoyl-β-D-galactopyranoside derivative (5) was used as the glycosyl acceptor and thiophenyl derivatives of D-galactose and D-mannose were used as donors respectively.

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A synthesis of 1, 2, 3, 4-tetrahydroquinolines (TQs) 13 with two and three methoxyl groups on the benzene ring, was achieved via intramolecular cyclization of N-aryl-N-[(phenylsulfinyl)propyl]formamides 7 utilizing the Pummerer reaction as a key step. The reaction was carried out by using trifluoroacetic anhydride (TFAA)(method A) or TFAA-BF₃·Et₂O (method B). The cyclization to 4-PhSTQs 8 proceeded effectively when the reaction center at the benzene ring was electronically activated by a methoxyl group. In the reaction of sulfoxide 7e having two OMe groups in the ortho- and para-positions, a different cyclization reaction leading to 1, 5-benzothiazepine derivative 9 was observed, indicating that the high uncleophilicity of the benzene ring caused the unexpected reaction prior to cyclization to 4-PhSTQs 8. This route starting from methoxyanilines provides an efficient and convenient method of TQ synthesis.

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A total synthesis of benzodioxole derivative 1 was achieved via a palladium(0)-catalyzed cross-coupling reaction in a 68% overall yield (4 steps). A novel series of benzodioxoles bearing a variety of aromatic and heterocyclic rings was also prepared and the antioxidative activity evaluated using in vitro model systems. Structure-activity studies revealed that i) intramolecular hydrogen-bonding in the phenol moiety reduced activity, ii) introduction of disubstituents at the ortho location relative to the phenol increased activity, and iii) the methylenedioxy function contributed to stabilization of the phenoxy radical. Among of these compounds, 5, 7-di-(4-methoxyphenyl)-4-methoxy-6-hydroxy-1, 3-benzodioxole (7p) was the most favorable agent and more potent than n-propyl gallate.

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Total synthesis of vibrioferrin (1), a siderophore, was achieved via a chiral dibenzyl citrate obtained by optical resolution. The citrate moity of vibrioferrin was determined to have the R configuration and one of the diastereomeric isomers (1b) of 1 did not exhibit siderophore activity.

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An efficient and stereoselective synthesis of the C13-C23 part (8) was achieved starting from methyl (R)-and (S)-3-hydroxy-2-methylpropionates (9) via coupling of the C13-C17 aldehyde (6), prepared by Evens asymmetric aldol reaction, with the C18-C21 iodoalkene (5b) by taking advantage of the 3, 4-dimethoxybenzyl protecting group.

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Alkylation of 8-oxoadenosine (13) with 4-benzyloxy-3, 5-dibromobenzyl bromide (20), followed by Dimroth rearrangement and acid hydrolysis, provided N-(3, 5-dibromo-4-hydroxybenzyl)-8-oxoadenosine (15). The 2'-deoxy version of this reaction sequence accomplished the first synthesis of N-(3, 5-dibromo-4-hydroxybenzyl)-8-oxodenine (16), which is the correct expression for marine ascidian purine aplidiamine.

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Silica gel and glass beads were modified using the acid chloride of metal-tetrakis(4-carboxyphenyl)porphine (M-TCPP) through a peptide bond, and an anion-exchange resin was modified with M-TCPP by electrostatic interaction and physical adsorption. The carriers modified with Co<3+>-TCPP proved to accelerate the following redox reaction : NADH+O₂→^^^(carriers modified with Co-TCPP)NAD⁺+H₂O₂.The formation of hydrogen peroxide was confirmed by means of a colored reaction. The glass beads medified with Co³⁺-TCPP exhibited the strongest activity among the tested carriers, and were expected to be useful practically as a solid catalyst for the formation of hydrogen peroxide from NADH.

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Two new phenylethanoid glycosides, ferruginoside A (3, 4-dihydroxy-β-phenylethoxy-O-β-D-glucopyranosyl-(1→6)-2-O-caffeoyl-β-D-glucopyranoside) and ferruginoside (3, 4-dihydroxy-β-phenylethoxy-O-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside) were isolated, along with the known compounds lugrandoside and trans-ferulic acid, from the aerial parts of D. ferruginea subsp. ferruginea. For structural elucidation of the isolates, chemical transformation (acetylation, methylation, alkaline hydrolysis), one and two dimensional (COSY, HMQC, HMBC, ROESY) NMR techniques and FAB-MS were used.

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Two new lupin alkaloids, (-)-N-(2-oxopyrrolidinomethyl)cytisine and (-)-N-(N-acetylaminomethyl)cytisine, were isolated together with 9 known alkaloids from Chinese Maackia hupehensis, which grows in the south of China. The alkaloidal constituents of M. hupehensis were shown to be comparable to those of the southern species of Japanese Maackia plants.

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A new benzofuroquinoline derivative, 3, 9-bis(N, N-dimethylcarbamoyloxy)-5H-benzofuro[3, 2-c]quinoline-6-one (KCA-098), shows poor oral absorption due to practical insolubility in water. In this study, a co-grinding technique employing a water-soluble polymer was used for improvement of the dissolution rate of KCA-098.Powder X-ray diffraction patterns and IR spectra of KCA-098 showed the conversion of the drug from a crystal state to an amorphous state by grinding with a polymer such as hydroxypropyl cellulose (HPC-SL) or polyvinylpyrrolidone (PVP K30). The particle size of KCA-098 was remarkably reduced to a submicron size by grinding with HPC-SL. The co-ground mixture with HPC-SL showed a repid dissolution rate and maintained supersaturation for more than 1 h. On the other hand, the co-ground mixture with PVP K30 showed rapid dissolution and supersaturation for a shorter period. These data suggest that the rapid dissolution rate was obtained by the conversion of the drug particles from a crystal to amorphous state by grinding with water-soluble polymers and that a reduction in particle size to the submicron level led to the maintenance of supersaturation due to good dispersion.

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Cyclobutyl nucleoside analogues containing guanine and 8-azaguanine (compounds 5-10) were perpared from (1R, cis)-3-aminomethyl-2, 2-dimethylcyclobutylmethanol (1). All were evaluated as anitviral and antitumoral agents in a variety of assay systems. Compounds 6 and 7 showed a noteworthy activity against a respiratory syncytial virus and compound 10 was moderately active against vaccinia virus. Only compound 5 showed some cytostatic activity.

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A method of the conversion of 2, 6-bis(tert-butyl)-4-methoxyphenyl dihydronaphthalenecarboxylates into substituted naphthalenes and tetrahydronaphthalenes was developed. Aromatization of substituted dihydronaphthalenecarboxylates with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone and subsequent treatment with ceric ammonium nitrate (CAN) gave the corresponding substituted naphthalenecarboxylic acid. Alternatively, hydrogenolysis and subsequent treatment with CAN provided a way to tetrahydronaphthalenemethanols in good yields.

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1, 4-Pyrimido- (2a), 1, 4-diazepino- (2b), and 1, 4-diazocino[1, 2, 3-gh]purine (2c) were designed as selective cAMP-phosphodiesterase 4 (PDE 4) inhibitors. The desired condensed-purines(2b, c) were synthesized by reaction of 7-aminoalkyl-3-propylpurine-2, 4-diones (6b, c) with hexamethyldisilazane by intramolecular cyclization via silylation-amination.

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Trifluoro or Chlorodifluoro analogs lf protoporphyrin, the compounds in the title, were synthesized for use in the diagnosis and therapy of cancer. 3-Or 8-acetyldeuteroporphyrin dimethyl esters (2 and 3) were iodinated with iodine in the presence of potassium carbonate to the corresponding iodo compounds (5 and 6). The iodo compounds (5 and 6) were treated with bis(trifluorovinyl)zinc in the presence of tetrakis(triphenylphosphine)-palladium to give trifluorovinyl derivatives (7 and 8) in good yields.Reduction of the acetyl group of 7 and 8 with sodium borohydride afforded the corresponding hydroxyethyl derivatives (9 and 10). Compounds (9 and 10) were dehydrated with methanesulfonyl chloride and triethylamine to give (trifluorovinyl)vinyldeuteroporphyrin dimethyl esters (11 and 12).Treatment of 5 and 6 with bis(1-chloro-2, 2-difluorovinyl)zinc in the presence of tetrakis(triphenylphosphine)palladium, followed by similar reactions as above gave (1-chloro-2, 2-difluorovinyl)-vinyldeuteroporphyrin dimethyl esters (17 and 18).

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An optically pure C-6 O-acyl side chain equivalent of zaragozic acid A, (2E, 4S, 6S)-4, 6-dimethyl-2-octenoic acid, which features a 1, 3-syn-dimethyl-substituted carbon chain, has been readily synthesized from (S)-2-methylbutanal using a combination of the Evans aldol reaction and the Ireland deoxygenation method.

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Straight chain compounds having a phenylisoserine unit and an oxetane ring at the α- and ω-position, respectively as extremely simplified analogues of taxol were prepared. None of these compounds showed promising tubulin inhibitory activity.

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From the whole plants of Gentiana Olivieri, three new bitter secoiridoid glycosides, olivierosides A (1), B (2) and C (3) were isolated together with the known compounds, gentiopicroside, sweroside, 6'-O-β-D-glucosylgen-tiopicroside, swertiapunimarin, eustomoside, eustomorusside and septemfidoside, and the structures of the new compounds were elucidated based on spectroscopic and chemical evidence.

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As a part of the search for biologically active plant products, M cells, which form a collagen fiber network in vitro after a prolonged culture period, were used. The n-BuOH-soluble fraction of a methanol extract of leaves of Premna subscandens exhibited promotion of collagen network formation by M cells. Extensive isolation work guided by a bioassay afforded a phenylethanoid, acteoside, as an active compound.

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A novel sesterterpenoid designated as nitiol (1), possessing enhancement activity of IL-2 gene expression in a human T cell line, was isolated from the Peruvian folk medicine "Hercampuri" (Gentianella nitida). The structure was elucidated by extensive spectroscopic investigation.

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Through bioactivity-guided fractionation, eight phorobol di-esters, including five new ones (1-5), were isolated from the seeds of Croton tiglium collected in Egypt. 12-O-Acetylphorbol-13-decanoate (6) and 12-O-decanoylphorobol-13-(2-methylbutyrate) (4) potently inhibited the HIV-1-induced cytopathic effect on MT-4 cells (IC₁₀₀ values of 7.6 ng/ml and 7.81 μg/ml, and CC₀ values of 62.5μg/ml and 31.3 μg/ml, respectively) without activating protein kinase C.

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Several thiazolidinedione derivatives (3-7) were designed and synthesized as candidate thyromimetic drugs. Among them, the dihydrogenated compounds, such as 5-2-[[4-(3-tert-butyl-4-hydroxyphenyl)oxy-3, 5-diiodophenyl]ethyl]-2, 4-thiazolidine-dione (6d) and its 3-isopropyl analog (7b), exhibited potent thyroid hormone receptor α1 (TRα1) activation activity.

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