Novel indeno[1,2-b]indoloquinones as inhibitors of the human protein kinase CK2 with antiproliferative activity towards a broad panel of cancer cell lines

Hundsdörfer, Claas; Hemmerling, Hans-Jörg; Hamberger, Janina; Borgne, Marc Le; Bednarski, Patrick J.; Götz, Claudia; Totzke, Frank; Jose, Joachim

doi:10.1016/j.bbrc.2012.06.068

Cited by 31 publications

(34 citation statements)

References 35 publications

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“…Molecules with a TPSA of Ͻ140 Å 2 are indicative of excellent bioavailability (60). According to the theoretical study carried out by de Toledo et al (61), the TPSA of most leishmanicidal drugs currently on the market is higher than this limit, which probably restricts their absorption and bioavailability.…”

Section: Chemistrymentioning

confidence: 99%

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Baquedano

Alcolea

Toro

et al. 2016

Antimicrob Agents Chemother

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A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED 50 ) values ranging from 0.45 to 1.27 M and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3=-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

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Section: Chemistrymentioning

confidence: 99%

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Baquedano

Alcolea

Toro

et al. 2016

Antimicrob Agents Chemother

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“…site which has been shown to widely overlap the hydrophilic ATP-binding site 16. EXPERIMENTAL SECTIONChemistry.…”

mentioning

confidence: 99%

Converting Potent Indeno[1,2-b]indole Inhibitors of Protein Kinase CK2 into Selective Inhibitors of the Breast Cancer Resistance Protein ABCG2

et al. 2014

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A series of indeno[1,2-b]indole-9,10-dione derivatives were synthesized as human casein kinase II (CK2) inhibitors. The most potent inhibitors contained a N(5)-isopropyl substituent on the C-ring. The same series of compounds was found to also inhibit the breast cancer resistance protein ABCG2 but with totally different structure-activity relationships: a N(5)-phenethyl substituent was critical, and additional hydrophobic substituents at position 7 or 8 of the D-ring or a methoxy at phenethyl position ortho or meta also contributed to inhibition. The best ABCG2 inhibitors, such as 4c, 4h, 4i, 4j, and 4k, behaved as very weak inhibitors of CK2, whereas the most potent CK2 inhibitors, such as 4a, 4p, and 4e, displayed limited interaction with ABCG2. It was therefore possible to convert, through suitable substitutions of the indeno[1,2-b]indole-9,10-dione scaffold, potent CK2 inhibitors into selective ABCG2 inhibitors and vice versa. In addition, some of the best ABCG2 inhibitors, which displayed a very low cytotoxicity, thus giving a high therapeutic ratio, and appeared not to be transported, constitute promising candidates for further investigations.

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“…[176][177] Thereafter, human protein kinase CK2 inhibition activity of the produced indeno [1,2-b]indole derivatives was evaluated and showed satisfactory results. [178][179] Li and co-workers discovered novel multicomponent reactions involving N-heteroannulations of enaminones 75, ninhydrin, and acid anhydride or aromatic amines to selectively produce multifunctionalized indeno [1,2-b]indoles with different substituted patterns 78 and 79 as a racemic mixture (Scheme 23). 180 The synthesis of tetrahydroindeno [2',1':4,5]pyrrolo [2,3-d]pyrimidinetrione derivatives 81, based on the addition reaction of ninhydrin and 6-aminouracils 80, was developed by Bazgir and coworkers (Scheme 24).…”

Section: -10mentioning

confidence: 99%

Ninhydrin in synthesis of heterocyclic compounds

Ziarani¹,

Lashgari²,

Azimian³

et al. 2015

Arkivoc

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Ninhydrin has been utilized in many heterocyclic preparations and considered as an important building block in organic synthesis. There is a wide range of reactions that include ninhydrin in the synthesis of heterocyclic compounds. This review highlights the advances in the use of ninhydrin as starting material in the synthesis of various organic compounds and drugs in a fully comprehensive way, from its first isolation in 1910 to the end of 2013. There is also a diversity of multi-component reactions of ninhydrin and we highlight the recent reports in this review.

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Novel indeno[1,2-b]indoloquinones as inhibitors of the human protein kinase CK2 with antiproliferative activity towards a broad panel of cancer cell lines

Cited by 31 publications

References 35 publications

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

Converting Potent Indeno[1,2-b]indole Inhibitors of Protein Kinase CK2 into Selective Inhibitors of the Breast Cancer Resistance Protein ABCG2

Ninhydrin in synthesis of heterocyclic compounds

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