Masatomo Iwao

Anticancer alkaloid lamellarins inhibit protein kinases.

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dual-specificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors.

Design and synthesis of lamellarin D analogues targeting topoisomerase I.

A general synthetic route to rationally designed lamellarin D analogues, 1-dearyllamellarin D (1) and 1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was prepared by palladium-catalyzed direct arylation of 12, which in turn was synthesized via C-2-selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions. Compound 22 was converted to a wide range of C-1-substituted analogues 2 via regioselective electrophilic substitution and palladium-catalyzed cross-coupling reactions.

Total Syntheses of Lamellarin D and H. The First Synthesis of Lamellarin-Class Marine Alkaloids

Abstract Total syntheses of marine polyaromatic alkaloids, lamellarin D ( 1 ) and H ( 2 ), are described. The pentacyclic lamellarin ring system was constructed by N -ylide mediated pyrrole ring formation and subsequent lactonization of 4 obtained by an assembly of known benzylisoquinoline 5 , benzoate 6 and ethyl bromoacetate.

Directed lithiation of 1-triisopropylsilylgramine: a short access to 3,4-disubstituted indoles

1-Triisopropylsilylgramine was lithiated regioselectively at C-4 by treatment with t-BuLi in ether at 0°C for 1 h. The lithiated species was trapped with a variety of electrophiles to furnish 4-functionalized gramine derivatives in good yields. Replacement of the triisopropylsilyl protecting group by a methyl group resulted in C-2 selective lithiation under the similar reaction conditions

A regiospecific synthesis of carbazoles via consecutive palladium-catalyzed cross-coupling and aryne-mediated cyclization

A regiospecific synthesis of carbazoles has been developed using palladium-catalyzed cross-coupling of N-(tert-butoxycarbonyl)-2-tributylstannylanilines with 2- or 3-bromochlorobenzene followed by aryne-mediated cyclization as the key reactions. The carbazole alkaloids, glycozolinine and glycozolidine, were synthesized using this procedure

New synthetic approach to pyrroloiminoquinone marine alkaloids. Total synthesis of makaluvamines A, D, I, and K

A new entry into pyrroloiminoquinone marine alkaloids, makaluvamines, has been developed. The key 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline intermediates 11 and 18 were prepared by aryne-mediated cyclization of the 4-chloro-6-methoxytryptamine derivatives 10 and 17, respectively. The requisite substituents at the indole 4- and 3-positions of 10 and 17 were efficiently assembled by sequential use of directed lithiation of 1-triisopropylsilyl-6-methoxygramine (6) and fluoride ion-induced elimination-addition of the methiodide of 4-chloro-1-triisopropylsilyl-6-methoxygramine (7) as key reactions.

Synthesis of bostrycoidin via directed lithiation of tertiary nicotinamide

Abstract The formal total synthesis of the antibiotic bostrycoidin 3 was achieved by using 4-selective lithiation of N , N -diisopropylnicotinamide 4b followed by condensation with N , N -dimethyl-2,3,5-trimethoxybenzamide 2f as a key reaction.

The first total synthesis of veiutamine, a new type of pyrroloiminoquinone marine alkaloid

Abstract The first total synthesis of veiutamine, a new type of pyrroroiminoquinone marine alkaloid bearing a p -hydroxybenzyl substituent at C-6, has been achieved. The key step of the synthesis is 6-selective functionalization of the 1,3,4,5-tetrahydropyrrolo[4,3,2- de ]quinoline nucleus via N -Boc-directed lithiation.

Methodology for the efficient synthesis of 3,4-differentially substituted indoles. Fluoride ion-induced elimination-addition reaction of 1-triisopropylsilylgramine methiodides

Abstract 1-Triisopropylsilylgramine methiodide reacted smoothly with a variety of nucleophiles in the presence of tetrabutylammmonium fluoride to give 3-substituted indoles. The 3,4-disubstituted indoles were efficiently synthesized by sequential use of 4-selective lithiation of 1-triisopropylsilylgramine and this new substitution reaction.

Directed lithiation of 1-(tert-butoxycarbonyl)indolines. A convenient route to 7-substituted indolines

1-(tert-Butoxycarbonyl)indolines were regioselectivity lithiated at 7-position with s-BuLi-TMEDA in ether or THF at −78°C. The lithiated species were reacted with a range of electrophiles to give 7-substituted indoline derivatives