DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

Kiakos, Konstantinos; Sato, Atsushi; Asao, Tetsuji; McHugh, Peter J.; Lee, Moses; Hartley, John A.

doi:10.1158/1535-7163.mct-07-0294

Cited by 24 publications

(24 citation statements)

References 68 publications

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“…1C), suggesting that they represent "stealthy" lesions that are not readily recognized by repair pathways. Hypersensitivity of ERCC1 or XPF mutant cells to amino-CBI-DEI was even lower than reported for the achiral amino-CBI compound AS-I-145, for which mutation of either gene results in 7-to 8-fold hypersensitivity of Chinese hamster ovary cells (45). This insensitivity to ERCC1/XPF removes an important mechanism of resistance to cross-linking agents (46).…”

Section: Discussionmentioning

confidence: 78%

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

Wilson

Stribbling

Pruijn

et al. 2009

Molecular Cancer Therapeutics

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Hypoxia represents an important therapeutic target in tumors because of the resistance of hypoxic cells to radiotherapy and chemotherapy and because it is more severe in many tumors than in normal tissues. Here, we describe a class of prodrugs, nitro-chloromethylindolines, which undergo hypoxia-selective activation by endogenous nitroreductases in tumor cells to form the corresponding amino compounds. The latter are chemically related to the cyclopropylindoline antitumor antibiotics and they share the same properties of sequence-selective DNA minor groove alkylation and high cytotoxic potency. Of three alkylating subunits investigated, the chloromethylbenzindoline (CBI) structure provided the most favorable prodrug properties: aerobic cytotoxic potency of the amines was approximately 90-to 3,000-fold higher than the corresponding nitro compounds, and the nitro compounds showed air/anoxia potency differentials of up to 300-fold. Selective alkylation of adenine N3 in calf thymus DNA by an amino-CBI was shown by characterization of the thermal depurination product; the same adduct was shown in hypoxic RIF-1 cells exposed to the corresponding nitro-CBI prodrug under hypoxic (but not oxic) conditions. The amino metabolite generated from a nitro-CBI by cells expressing Escherichia coli nfsB nitroreductase in multicellular layer cultures was shown to elicit bystander killing of surrounding cells. Nitro-CBI prodrugs were >500-fold less toxic to mice than amino-CBIs by i.p. administration and provided selective killing of hypoxic cells in RIF-1 tumors (although only at maximally tolerated doses). Nitro-CBIs are novel lead hypoxia-activated prodrugs that represent the first examples of hypoxiaselective generation of potent DNA minor groove alkylating agents.

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Section: Discussionmentioning

confidence: 78%

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

Wilson

Stribbling

Pruijn

et al. 2009

Molecular Cancer Therapeutics

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“…All cell lines were maintained in DMEM (PAA) supplemented with 2 mM L-glutamine (PAA) and 10% fetal bovine serum (PAA). Growth inhibition was determined in both exponentially growing and confluent cells using the SRB assay as previously described (Kiakos et al, 2007).…”

Section: Chemicalsmentioning

confidence: 99%

Nuclear Localization and Gene Expression Modulation by a Fluorescent Sequence-Selective p-Anisyl-benzimidazolecarboxamido Imidazole-Pyrrole Polyamide

Kiakos

Pett

Satam

et al. 2015

Chemistry & Biology

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Synthetic pyrrole (P)-imidazole (I) containing polyamides can target predetermined DNA sequences and modulate gene expression by interfering with transcription factor binding. We have previously shown that rationally designed polyamides targeting the inverted CCAAT box 2 (ICB2) of the topoisomerase IIα (topo IIα) promoter can inhibit binding of transcription factor NF-Y, re-inducing expression of the enzyme in confluent cells. Here, the A/T recognizing fluorophore, p-anisylbenzimidazolecarboxamido (Hx) was incorporated into the hybrid polyamide HxIP, which fluoresces upon binding to DNA, providing an intrinsic probe to monitor cellular uptake. HxIP targets the 5'-TACGAT-3' sequence of the 5' flank of ICB2 with high affinity and sequence specificity, eliciting an ICB2-selective inhibition/displacement of NF-Y. HxIP is readily taken up by NIH3T3 and A549 cells, and detected in the nucleus within minutes. Exposure to the polyamide at confluence resulted in a dose-dependent upregulation of topo IIα expression and enhanced formation of etoposide-induced DNA strand breaks.

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“…(2). Indolinone based drugs entered in clinical trials (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). treatment.…”

Section: Indolinones That Have Been Entered In Clinical Studiesmentioning

confidence: 99%

“…Substituted indolin-2-ones have been identified as a versatile scaffold for the development of protein kinase inhibitors which exhibit selectivity toward different RTKs by altering the various substituents [15]. Pyrrole-indoline-2-ones were among the first structures identified as kinase inhibitors and have been intensively studied for the inhibition of VEGFR, ac-Kit, FLT3, PDGFR-R/ , and CSF1R [16].…”

Section: Introductionmentioning

confidence: 99%

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Prakash¹,

Raja

2012

MRMC

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Kinases are probably the most important signaling enzymes, which represent about 20% of the druggable genome. Currently, more than 150 kinases are known. So, kinase inhibition therapy has become a very important area of drug research since most of our diseases are related to intra or intercellular signaling by kinases. Indole alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, antitumor. Among this chemical family, indolinone displays very promising antitumor properties by inhibiting various kinase families. These small molecules have a low molecular weight and most of them bind to protein kinases competing with ATP for the ATP-binding site. This review focuses on the indolinone based drugs approved for the treatment of cancer, drugs under clinical trial and then chemical diversity of various synthetic analogues of indolinone and their metabolites as various kinase inhibitors. This review also focused on structural activity relationship (SAR), mechanisms of action and biological targets through which indolinone and its derivatives display their antitumor activity.

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DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

Cited by 24 publications

References 68 publications

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

Nitro-chloromethylbenzindolines: hypoxia-activated prodrugs of potent adenine N3 DNA minor groove alkylators

Nuclear Localization and Gene Expression Modulation by a Fluorescent Sequence-Selective p-Anisyl-benzimidazolecarboxamido Imidazole-Pyrrole Polyamide

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

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