Eiichi Sugino

A Novel Total Synthesis of Antibiotic Carbazole Alkaloid Carbazomycin G

Abstract A total synthesis of carbazomycin G ( 1 ) has been newly completed in seven steps. The 1,3-dioxygenated carbazole ( 4 ) via the 3-methoxy-1-methoxymethyloxycarbazole ( 11 ) as a synthetic precursor was synthesized by using the allene-mediated electrocyclic reaction of a 6π electron system generating from the 2 -propargylindole derivative ( 10 ), which was derived from the 3-vinylindole ( 8 ) in three steps. Finally, the oxidation of the phenol ( 4 ) followed by the addition of methyl lithium to the carbazole-1,4-quinone ( 3 ) provided carbazomycin G ( 1 ).

Total syntheses of carazostatin and hyellazole by allene-mediated electrocyclic reaction

Abstract The free radical scavenger carazostatin and the marine alkaloid hyellazole have been synthesized by a new type of allene-mediated electrocyclic reaction involving the indole 2,3-bond as a key step.

The first total synthesis of the novel β-carboline alkaloid oxopropaline G

Abstract The first total synthesis of the new type of cytocydal β-carboline alkaloid oxopropaline G was achieved in 12 steps.

Total synthesis of aaptamine of potent α-blocking activity via thermal cyclization of 1-azahexatriene systems

The total synthesis of the marine alkaloid aaptamine (1), 1H-benzo[de][1,6]naphthyridine, has been completed, based on the thermal cyclization of the 1-azahexatriene system, the key intermediate for the construction of the isoquinoline moiety. 5-Nitroveratraldehyde (7) is converted, via a Wittig reaction, into the nitrostyrene (8). Reduction of (8) to the aniline (9) and subsequent treatment of (9) with ethyl 2-formylacetate gives the enamino ester (10). Preparation of the quinolone nucleus is achieved by heating compound (10) in diphenyl ether, which affords the N-benzylquinolone (12) along with the quinoline (13). Treatment of an inseparable mixture of (12) and (13) with hydroxylamine gives the debenzylated quinolone oxime (11), methylation of which affords a separable mixture of the N,O-dimethyl quinolones (14) and (15). The methyloxime (14)(the 1-azahexatriene system) when heated in o-dichlorobenzene gives the unnatural 1 -methylaaptamine (3). In a similar way, benzylation of (15) affords the N,O-dibenzyl quinolone derivatives (16) and (17). The benzyloxime (16) when heated in o-dichlorobenzene affords N-benzylaaptamine (18). Subsequent cleavage of the N-benzyl protecting group with concentrated hydrochloric acid gives aaptamine hydrochloride (1).

The first synthesis of mutagenic trp p 1 via the electrocyclic reaction of 1 azahexa 1 3 5 triene system

The first total synthesis of Trp-P-1 has been completed by the thermal electrocyclic reaction of 1-azahexa-1,3,5-triene system

Anti-angiogenic activity of a novel synthetic agent, 9α-fluoromedroxyprogesterone acetate

9Alpha-fluoromedroxyprogesterone acetate (FMPA) is a novel synthetic analog of medroxyprogesterone acetate (MPA), widely used as therapeutic agent for breast and endometrium cancers. FMPA showed almost the same binding affinities to the progesterone and glucocorticoid receptors as MPA. In the rabbit corneal assay, FMPA, MPA and fumagillin significantly inhibited the angiogenic response induced by rat mammary tumor at doses of 0. 1, 1 and 50 microg/pellet, respectively, so FMPA showed greater anti-angiogenic activity than MPA and fumagillin. In the mouse dorsal air sac method, FMPA inhibited the mouse sarcoma 180 cell-induced angiogenesis by oral administration at a dose of 200 mg/kg. FMPA inhibited the activity of plasminogen activator (PA) in bovine endothelial cells. These results suggest that FMPA may be useful for diseases associated with angiogenesis by oral administration.

The new approach to antibiotic carbazomycins. The formal total synthesis of carbazomycins A and B

Deoxycarbazomycin B has been synthesized in a four step sequence. The key reaction has been the thermal electrocyclic reaction of 1,3,5-hexatriene system involving the indole 2,3-bond

SYNTHESIS OF A NEW POTENT ANTI-ANGIOGENIC AGENT, 17α-ACETOXY-9α-FLUORO-6α-METHYLPROGESTERONE

A new anti-angiogenic agent, 17 alpha-acetoxy-9 alpha-fluoro-6 alpha-methylprogesterone (9 alpha-fluoromedoroxyprogesterone acetate [FMPA, 9] was synthetized in a 10-step sequence. FMPA (9) had about two orders of magnitude stronger anti-angiogenic activity than medroxyprogesterone acetate (MPA), as estimated in a bioassay involving chorioallantoic membranes of growing chick embryos.

Inhibition by 9α-fluoromedoroxyprogesterone acetate (FMPA) against mammary carcinoma induced by dimethylbenz[a]anthracene in rats and angiogenesis in the rabbit cornea – comparison with medroxyprogesterone acetate (MPA)

Medroxyprogesterone acetate (MPA) is currently used therapeutically in the treatment of mammary and endometrial carcinomas. In order to develop a more potent and useful drug, we synthesized the novel compound, 9alpha-fluoromedoroxyprogesterone acetate (FMPA), by fluorinating MPA, and we also previously reported that FMPA displays more potent anti-angiogenic activity in the chorioallantoic membrane assay than MPA. In the present study, we investigated (1) the effects of FMPA on rat mammary carcinomas induced by dimethylbenz[a]anthracene (DMBA) to determine the anti-tumor activity, (2) the effect on angiogenesis in rabbit corneal assays, and (3) compared these results with those for MPA. FMPA inhibited the growth of mammary carcinomas in a dose-dependent manner (7.5, 30 and 120 mg/kg). Almost complete involution of the carcinomas was observed at doses of 30 and 120 mg/kg. MPA also inhibited the growth of carcinomas at doses of 30 and 120 mg/kg, but no involution of carcinomas was observed even at 120 mg/kg. FMPA significantly and MPA to a lesser degree inhibited carcinogenesis at 120 mg/kg within their treatments. In rabbit corneal assays, FMPA significantly inhibited angiogenesis (IC50 value=0.085 microg/pellet). MPA also significantly inhibited angiogenesis (IC50 value=0.60 microg/pellet). From these results, we conclude that FMPA is potentially more effective in the treatment of mammary carcinomas than MPA.

Pharmacokinetics of 9α-fluoromedroxyprogesterone acetate in rats : Comparison with Medroxyprogesterone acetate

Medroxyprogesterone acetate (MPA) is widely used in endocrine therapy for breast cancer and other diseases. Recently, it has been demonstrated that 9α‐fluoromedroxyprogesterone acetate (FMPA) also has anti‐tumour activity in chemical‐induced rat mammary tumour and its activity is greater than that of MPA. In the present study, the physico‐chemical properties of FMPA and MPA and their pharmacokinetics in female rats were investigated. Partition coefficients (log P) of FMPA and MPA were 3.1 and 3.8, respectively, while the solubilities of FMPA and MPA in phosphate buffer saline were 3.8 and 1.1 μg/mL, respectively. When the two agents were intravenously or orally administered into female rats, there was no significant difference between their plasma concentrations. However, unmetabolized drug excreted into urine accounted for 4.7 and 0.7% of the intravenous dose of FMPA and MPA, respectively. The free fraction of FMPA in rat plasma was approximately four times that of MPA. Assuming the well‐stirred model, hepatic intrinsic clearances of FMPA and MPA were estimated to be 64 and 293 L/h per kg, respectively. In addition, the free fraction of FMPA in blood is estimated to be higher than that of MPA, which may explain the higher anti‐tumour activity. Copyright