Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCβ-selective inhibitors

Tanaka, Masahiro; Sagawa, Shoichi; Hoshi, Jun‐ichi; Shimoma, Fumito; Yasue, Katsutaka; Ubukata, M.; Ikemoto, Tomoyuki; Hase, Yasunori; Takahashi, Mitsuru; Sasase, Tomohiko; Ueda, Nobuhisa; Matsushita, Mutsuyoshi; Inaba, Takashi

doi:10.1016/j.bmc.2006.05.033

Cited by 40 publications

(18 citation statements)

References 32 publications

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“…In 2006, Tanaka et al reported conformationally restricted 3-anilino-4-(3-indolyl) maleimide derivatives acting as PKC-b selective inhibitors and possessing oral bioavailability. Among these, compounds having a fused fivemembered ring at the indole 1,2-position exhibited activity at a very low concentration and had ameliorative effects in a rat diabetic retinopathy via the oral route and showed good oral bioavailability [10,53]. In 2009, Wagner et al reported a series of indolylquinazolylmaleimides, which are novel maleimide-based derivatives.…”

Section: Pkc Inhibitorsmentioning

confidence: 97%

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Protein kinase C βII in diabetic complications: survey of structural, biological and computational studies

Sobhia¹,

Grewal²,

Bhat³

et al. 2012

Expert Opinion on Therapeutic Targets

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Section: Pkc Inhibitorsmentioning

confidence: 97%

“…In 2011, Li et al reported initial SAR studies on a series of novel pyrrolopyrazole-based PKC-bII inhibitors from high throughput screening [55]. Table 2 lists the molecules reported in SAR studies [10,11,18,[48][49][50][51][52][53][54][56][57][58].…”

Section: Pkc Inhibitorsmentioning

confidence: 99%

Protein kinase C βII in diabetic complications: survey of structural, biological and computational studies

Sobhia¹,

Grewal²,

Bhat³

et al. 2012

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…Biological data (IC 50 ) of the molecules reported by Masahiro Tanaka et al has been used in this study (Tanaka et al, 2004(Tanaka et al, , 2006. The compounds were evaluated for their in vitro enzyme inhibitory activity against PKCbII.…”

Section: Selection Of Datasetmentioning

confidence: 99%

“…Maleimide forms hydrogen bonds with the protein and two aromatic rings bound to the 3-and 4-positions of the maleimide filling hydrophobic regions of the protein (Grodsky et al, 2006). One of the indoles of Ro-31-6233 (Chart 1) when replaced with aliphatic amines or aniline showed selective PKCbII inhibitory activity (Tanaka et al, 2004(Tanaka et al, , 2006. Another novel series of macrocyclic bis-indolyl maleimides was found to have inhibitory action on both PKCb and GSK-3 b (Zhang et al, 2003;Shen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

2D and 3D QSAR analyses to predict favorable substitution sites in anilino-monoindolylmaleimides acting as PKCβII selective inhibitors

2010

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Diabetic cardiomyopathy (DCM) is a clinical condition, diagnosed when ventricular dysfunction develops in diabetic patients without coronary atherosclerosis and hypertension. Intensive studies on pathogenesis of DCM show PKCbII as one of the mediators, responsible for developing DCM. 2D-QSAR (HQSAR) and 3D-QSAR (CoMSIA) studies were performed on a dataset of 42 anilinomonoindolylmaleimides acting as PKCbII selective inhibitors. Among the different alignment strategies used for CoMSIA study FlexS was found to be the best alignment method. Conformational search was performed for a few molecules to obtain the best model. CoMSIA analysis gave information about sites of favorable substitutions and steered us to assume that alkyl amine substitution on the pharmacophore would be a favorable substituent for improving the biological activity. From HQSAR studies we could extrapolate the presence of tertiary acceptor group may probably be responsible for increase in the activity whereas occurrence of cyclic ring structures would lead to decrease in the activity.

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“…Indolylmaleimides (e.g., JTT 010), were reported to exhibit remarkable PKC inhibition (Tanaka et al, 2006). We reasoned that by introducing nitrogen atoms into the indolylmaleimide ring, one might be able to enhance the binding of the compounds to PKC.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives

et al. 2011

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In an attempt to develop potent and selective antitumor agents, a series of novel 3-amino-4-indolylmaleimides were designed and synthesized. The reaction showed high regioselectivity. The structure of compound 7a was determined by an X-ray single crystal diffraction method. The cytotoxicities of the title compounds were evaluated against HeLa, SMMC 7721 and HL 60 cancer cell lines by a standard MTT assay in vitro. The pharmacological results showed that some of the title compounds displayed moderate or high cytotoxic activity against the tested cell lines. Compound 7d was the most promising compound against the tested cancer cell lines. Structure-activity relationships are discussed based on the experimental data obtained. A hydroxyethylamino group at the 3-position in the side chain of indolylmaleimide is associated with an increase in cytotoxicity.

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Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCβ-selective inhibitors

Cited by 40 publications

References 32 publications

Protein kinase C βII in diabetic complications: survey of structural, biological and computational studies

Protein kinase C βII in diabetic complications: survey of structural, biological and computational studies

2D and 3D QSAR analyses to predict favorable substitution sites in anilino-monoindolylmaleimides acting as PKCβII selective inhibitors

Synthesis and cytotoxicity of novel 3-amino-4-indolylmaleimide derivatives

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