Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives.

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M.

The enantioselective total synthesis of a beta-carboline alkaloid, (S)-(-)-dichotomine C.

The first enantioselective synthesis of a beta-carboline alkaloid, dichotomine C, possessing antiallergic effects, was achieved by constructing a beta-carboline framework based on the microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system, followed by the Sharpless asymmetric dihydroxylation.

Lipase-catalyzed asymmetric synthesis of desprenyl-carquinostatin A and descycloavandulyl-lavanduquinocin.

An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2), has been established. Lipase QLM (Meito) catalyzed enantioselective acetylation of the racemic alcohol 6 gave the (-)-acetate 7 and the (+)-alcohol 6 with high enantioselectivity. The absolute stereochemistry of the (-)- and (+)-alcohol 6 have been determined to be R- and S-configurations, respectively, by the advanced Mosher method. In the same manner, the (-)-acetate 13 and the (+)-alcohol 12 have been obtained from the racemic alcohol 12. The (R)-(-)-acetate 13, derived from the (R)-(-)-acetate 7, was the same as the (-)-acetate 13, which has been determined to be (R)-configuration. Oxidation of the (R)-(-)-acetate 13 followed by hydrolysis afforded (R)-(-)-6-desprenyl-carquinostatin [and (R)-(-)-6-descycloavandulyl-lavanduquinocin] 3. In addition, oxidation of the (S)-(+)-alcohol 12 provided (S)-(+)-3, which is the enantiomer of 6-desprenyl-carquinostatin A (R)-(-)-3.

Suppression of laser-induced choroidal neovascularization by subconjunctival injection of 9alpha-fluoromedroxyprogesterone acetate (FMPA), an anti-angiogenic agent, in rats.

9alpha-Fluoromedroxyprogesterone acetate (FMPA) is a synthetic analog of medroxyprogesterone acetate (MPA). FMPA exhibited more potent anti-tumor and anti-angiogenic activities in some assay systems than the parent agent, MPA. Exudative age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). Anecortave acetate, an angiostatic steroid, is clinically efficacious in patients with exudative AMD. Betamethasone is an anti-angiogenic steroid. Therefore, we examined the effects of FMPA, anecortave acetate and betamethasone on laser-induced CNV in rats. Anecortave acetate and betamethasone were included as positive controls. Crypton laser was applied to the fundus in Brown Norway rats. Laser photocoagulations were performed in each eye between the major retinal vessels of the superior retina. Subconjunctival injection of FMPA, anecortave acetate or betamethasone was performed once just after the photocoagulation (on day 0). The incidence of CNV formation was evaluated by fluorescein angiography (FAG) on day 14. On the next day, examination of the retinal function was performed by electro retinogram (ERG). Subconjunctival injection of FMPA at doses of 300, 1000 and 3000 microg/eye dose-dependently inhibited the incidence of CNV formation. Significant differences were observed at doses of 1000 and 3000 microg/eye of FMPA as compared with the control group. Anecortave acetate and betamethasone significantly inhibited the incidence of CNV formation. FMPA at the doses used in this study did not affect the retinal function in rats, as determined by ERG. FMPA appeared to be effective in a rat model of CNV, so it was demonstrated that FMPA might be useful in the treatment of AMD.

Synthesis and anti-tumor activity of a fluorinated analog of medroxyprogesterone acetate (MPA), 9alpha-fluoromedroxyprogesterone acetate (FMPA).

We synthesized 9alpha-fluoromedroxyprogesterone acetate (FMPA) in order to test whether it is a more potent anti-angiogenic agent than medroxyprogesterone acetate (MPA), which has been widely used as a therapeutic agent for breast and endometrium cancers. FMPA was previously synthesized in 10 steps (total yield: 1%). An efficient synthesis of FMPA has been achieved in 6 steps (total yield: 12%). We examined the anti-tumor effect of FMPA, complexed with dimethyl-beta-cyclodextrin (DM-beta-CyD), on rat mammary carcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA). FMPA showed great anti-tumor effect on DMBA-induced rat mammary carcinomas.

Synthesis of the new furo[3,2-h]isoquinoline alkaloid, TMC-120B from Aspergillus ustus.

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus together with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the appropriate 3,7,8-trisubstituted isoquinoline framework (23) based on a thermal electrocyclic reaction of the 1-aza 6pi-electron system involving the benzene double bond. In addition, the microwave assisted electrocyclic reaction of this system was newly performed.

The absolute configuration of (+)-oxopropaline D by theoretical calculation of specific rotation and asymmetric synthesis.

The specific optical rotations of (R)-oxopropaline D calculated by two ab initio MO methods were +52+/-31 degrees and +61+/-29 degrees, respectively, and (+)-oxopropaline D (3) was presumed to have an R-configuration. On the basis of this theoretical result, the reaction of 1-litio-beta-carboline with (R)-glyceraldehyde acetonide followed by oxidation with MnO(2) gave (R)-oxopropaline D acetonide (4a), which was consistent with the previously synthesized (+)-oxopropaline D acetonide (4) in all respects. From the results of theoretical calculations and the experimental synthesis, we determined that natural (+)-oxopropaline D (3) has an R-configuration.