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Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives.

ABSTRACT: A novel strategy for the synthesis of (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (1a-d) via (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), starting from alendronate has been developed with reasonable 51-77% overall yields. Intermediate products, (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), were prepared in water with reasonable to high yields (52-94%).

SUBMITTER: Turhanen PA

PROVIDER: S-EPMC1408082 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives.

Turhanen Petri A PA Vepsäläinen Jouko J JJ

Beilstein journal of organic chemistry 20060224 1

A novel strategy for the synthesis of (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (1a-d) via (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), starting from alendronate has been developed with reasonable 51-77% overall yields. Intermediate products, (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), were prepared in water with reasonable to high yields (52-94%). ...[more]

PMID: 16542011

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Project description:In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-d]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3K? inhibitors. Among them, the indole derivative 3 is one of the most selective PI3K? inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3K?/? inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3K? inhibitors. After the reduction of nitro group in N-(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N-(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6, the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives 15a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4, these 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3K? inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3K?/? inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3K?. Moreover, the introducing of a fluorine atom at the 7-position of the 2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3K? inhibitory activity. In agreement with their high PI3K? selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.

Dataset Information

Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives.

Publications

Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives.

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