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SummaryAnaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.

An effective and convenient protocol has been developed for the conversion of d -glucose and 6-O-α- d -glucopyranosyl- d -fructose (palatinose®, isomaltulose) into 5-[(1′S)-1′,2′-dihydroxyethyl]-1-phenylpyrazole-3-carboxaldehyde (4) and 5-[(1S)-2-(α- d -glucopyranosyloxy)-1-hydroxethyl])-1-phenylpyrazole-3-carboxaldehyde (5), key steps being the acetic anhydride-promoted dehydrative cyclization of the respective phenylosazones, and subsequent liberation of the N-acetylphenylhydrazone-blocked aldehyde function. Exploitation of the ensuing chemistry of 4 and 5 led to a variety of pyrazole building blocks with a diverse level of hydrophilic substituents (hydroxymethyl, dihydroxyethyl or glucosyl residues) and useful functional groups, such as chloro, cyano, aminomethyl, vinyl and acryloyl moieties.

The larvicidal activity of 1- tert -butyl-1-(2-chlorobenzoyl)-2-(substituted benzoyl)hydrazines was measured against the rice stem borer ( Chilo suppressalis) in the presence of piperonyl butoxide, an inhibitor of oxidative metabolism. Variations in the activity were quantitatively examined by use of physicochemical substituent parameters and regression analysis. The results indicated that the hydrophobicity of substituents is favorable in general but the bulkiness of substituents is unfavorable position-specifically. The most favorable substitution pattern is the para substitution with lower alkyls and halogens. Compounds in which substitution patterns are simultaneously optimized in two benzene rings in the molecule were designed and prepared according to the present and previous quantitative analyses. Some of them, including 1- tert -butyl-1-(3,5-dichloro- and 3,5-dimethylbenzoyl)-2-(4-ethylbenzoyl)hydrazines, the second being RH-5992, were about 20-30 times as larvicidal as the unsubstituted compound, RH-5849, against the rice stem borer.

The effects of 20-hydroxyecdysone and dibenzoylhydrazine insecticides related to RH-5849 (1,2-dibenzoyl-1- tert -butylhydrazine) were tested on the integument fragments of the rice stem borer, Chilo suppressalis . The fragments were first exposed 10 the compounds. Then cultured in fresh medium containing 14 C-labeled N -acetylglucosamine ([ 14 C]GluNAc). These compounds enhanced the incorporation of [ 14 C]GluNAc into the integument fragments in a dose-dependent manner in the range of 10 −6 ∼ 10 −7 M . When the concentration of the compounds was above this range or if the fragments were exposed for over 48 hr, the degree of the enhancement was smaller than that observed under the optimum conditions. By extracting the cultured integument in hot alkali, the incorporated radioactivity was partially released. The degree of this was not affected by the concentration of the compounds. The ability of compounds to enhance the incorporation of [ 14 C]GluNAc into the cultured integument was evaluated in terms of the concentration required to incorporate half maximum of the control level.

The larvicidal activity of benzoylphenylureas with various multiple substitution patterns at the anilide moiety including chlorfluazuron and teflubenzuron was estimated against the rice stem borer, Chilo suppressalis , under conditions in which the oxidative metabolism was eliminated as far as possible by using piperonyl butoxide. The activity was quantitatively analyzed using physicochemical parameters of substituents at each of the anilide aromatic positions. The results indicated that the total hydrophobicity (with an optimum) and electron-withdrawing ability of substituents are favorable to the activity. Small size of substituents was advantageous but the size effect was specific to their positions. The molecular mode of interaction with the possible receptor was suggested so that the compounds may recognize the possible receptor wall from the side of the vicinal pair of ortho and meta positions occupied by smaller substituents, and the receptor site corresponding to the ortho substituent is hydrophilic and constrained.