Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors

Becknell, Nadine C.; Zulli, Allison L.; Angeles, Thelma S.; Yang, Shi; Albom, Mark S.; Aimone, Lisa D.; Robinson, Charles Alexander; Chang, Hong; Hudkins, Robert L.

doi:10.1016/j.bmcl.2006.07.066

Cited by 16 publications

(7 citation statements)

References 19 publications

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“…Except for some compounds with no activity or unclear activity, 80 indolocarbazole compounds from 4 references [6–9] are selected as the training set, among which 15 compounds are randomly chosen as the testing set (the testing set is marked by *). According to research practice, all original IC 50 values (nmol/L) were converted to negative logarithm of IC 50 (pIC 50 ) and used as dependent variable in our 3D-QSAR study.…”

Section: Methodsmentioning

confidence: 99%

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Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Tian

et al. 2011

IJMS

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Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q2 = 0.823, r2 = 0.979; CoMSIA model: q2 = 0.804, r2 = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisf actory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.

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Section: Methodsmentioning

confidence: 99%

“…Recently, a novel series of indolocarbazole was reported as a kind of receptor tyrosine kinase inhibitor targeted to Tie-2 [6–9]. However, the QSAR focuses on indolocarbazole series compounds as Tie-2 inhibitors have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Tian

et al. 2011

IJMS

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“…(81) Acts as a Tie-2 and VEGFR-2 dual inhibitor with IC 50 values of 11 and 5 nM, respectively, with good cellular activity and oral bioavailability. It has also been evaluated against murine angiosarcoma in nude mice, resulting in activity, but also toxicity [174].…”

Section: Indenopyrrolocarbazolones and Similar Derivativesmentioning

confidence: 99%

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Schenone¹,

Bondavalli²,

Botta

2007

CMC

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Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.

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“…Several literature studies reported that molecules with a carbazolic moiety are able to inhibit different TKs [109][110][111][112][113][114]. (61).…”

Section: Carbazoles As Tyrosine Kinases Inhibi-torsmentioning

confidence: 99%

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

Ceramella

Iacopetta

Barbarossa

et al. 2020

MRMC

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Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

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Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors

Cited by 16 publications

References 19 publications

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Combined 3D-QSAR and Docking Modelling Study on Indolocarbazole Series Compounds as Tie-2 Inhibitors

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

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