Stereoselective oxidation by thionyl chloride leading to the indeno[1,2-c]isoquinoline system

Cushman, Mark; Cheng, Leung

doi:10.1021/jo00413a036

Cited by 75 publications

(124 citation statements)

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“…Indenoisoquinolines were first synthesized in 1978 (28) and studied as topoisomerase I (topI) inhibitors with advantageous properties compared to camptothecins, known TopI inhibitors. Additional activities are also known, such as induction of cell cycle arrest, overcoming multidrug-resistance, and enhancement of the differentiation-inducing activity of retinoids (29–31).…”

Section: Discussionmentioning

confidence: 99%

Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Park

Kondratyuk

Morrell

et al. 2011

Cancer Prevention Research

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Retinoid X receptor (RXR) has been targeted for the chemoprevention and treatment of cancer. To discover potential agents acting through RXRs, we utilized an RXR response element-luciferase reporter gene assay. Following extensive screening, 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride (AM6-36) was found to induce RXRE-luciferase activities. AM6-36 inhibited cyclooxygenase-2 expression and anchorage-independent growth with 12-O-tetradecanoylphorbol 13-acetate-stimulated JB6 Cl41 cells, induced the expression of CD38 in HL-60 cells, and attenuated the growth of N-methyl-N-nitrosourea-induced mammary tumors in rats. Consistent with other reports describing the anti-proliferative effects of RXR agonists in breast cancers, AM6-36 showed growth inhibition with cultured MCF7 breast cancer cells, accompanied by G2/M phase arrest at lower concentrations and enhanced S phase arrest at higher concentrations. Based on DNA microarray analysis, AM6-36 up-regulated the expression of CDKN1A, a target gene of RXR, by 35-fold. In accord with this response, the expression of the corresponding protein, p21WAF1/CIP1, was increased in the presence of AM6-36. Induction of p21 by AM6-36 was abrogated following transient knock-down of RXRα, demonstrating the effect of AM6-36 on the expression of p21 is closely related to modulation of RXRα transcriptional activity. Intestinal permeability was suggested with Caco-2 cells, and limited metabolism resulted when AM6-36 was incubated with human liver microsomes. Oral administration with rats resulted in 0.8 μg/ml, 4.3 μg/g, and 0.3 μg/g in serum, liver, and mammary gland, respectively. In sum, these data suggest AM6-36 is a promising lead for the treatment or prevention of breast cancer and provide a strong rationale for testing in more advanced anti-tumor systems.

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Section: Discussionmentioning

confidence: 99%

Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Park

Kondratyuk

Morrell

et al. 2011

Cancer Prevention Research

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“…CPT was obtained from the Drug Synthesis and Chemistry Branch, National Cancer Institute (Bethesda, MD). The syntheses of NSC 314622 (Cushman and Cheng, 1978), MJ-III-65 (NSC 706744) (Cushman et al, 2000), and the monomer NSC 725671 (Nagarajan et al, 2004) have been described previously. The synthesis of the bisindenoisoquinoline NSC 727357 will be described elsewhere (Nagarajan, et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

Antony

Agama²,

Hollingshead³

et al. 2006

Mol Pharmacol

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Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G 1 with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744,aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.

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“…The indenoisoquinolines selectively trap Topoisomerase 1/DNA cleavage complexes (Cushman and Cheng 1978) in a manner that is more persistent than the complexes induced by camptothecins. The indenoisoquinolines target different genomic sites (break DNA at different sequences) than camptothecins and therefore may potentially exhibit a different spectrum of anti-cancer activity.…”

Section: Indenoisoquinolinesmentioning

confidence: 99%

DNA Damaging Drugs

Weber

2015

Molecular Therapies of Cancer

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The classical anti-cancer agents comprise cytotoxic compounds. Mostly, these drugs act by exerting DNA damage. In essence, there are two major response phenotypes available to a cell upon DNA damage, such as a chemotherapeutic drug action, -to arrest the cell cycle and repair the damage, -to initiate a pathway to apoptosis (programmed cell death).In either scenario, the uncontrolled growth of the tumor cells is curtailed. The major limitation of the cytotoxic anti-cancer drugs is the tumor non-specific action, and the suppression of all rapidly dividing cells 1 . Alkylating AgentsAlkylating agents 2 are electrophilic and bind covalently to electron-rich functional groups of various target molecules via first-order or second-order nucleophilic substitutions (nucleophiles are electron-rich molecules or ions, such as OH − , H 2 O, halogenides, alcohols, thiols and amines). The first order reactants include aromatic and aliphatic nitrogen and sulfur mustards. Second order reactants include ethylene 1 Because the desired drug actions (damage to rapidly proliferating cancer cells) and the adverse effects (damage to rapidly proliferating healthy cells) are identical in targets and mechanisms, they are not separable. 2 Alkyl designates a functional group (a "side chain") that consists solely of single-bonded carbon and hydrogen atoms. Alkylating anticancer agents attach alkyl groups to biomolecules. imines and epoxides, alkylmethane sulfonates of the busulfan (Myleran) type, and α-halogenated acids, ketones, and their derivatives.-For first-order reactions, the rate limiting step is the ionization of the alkylating agent to form a positively charged carbonium ion, which then rapidly reacts with water, or a negative center, or a nucleophilic center. Within DNA and RNA, the most reactive site is the N 7 position of guanine ( Fig. 2.1). In DNA, this is followed by N 3 of adenine, N 1 of adenine, N 1 of cytosine, and N 7 of adenine (Table 2.1). The rate limiting step of the reaction is the formation of positively charged cyclic immonium ions, whereas the rate of the reaction is essentially independent of the nature and concentration of the nucleophilic target being attacked. -For second order nucleophilic substitutions, both reactants interact to form a transition complex. No carbonium ion is formed. The rate of the reaction depends on both concentrations, with bond strengths, electron affinity, and accessibility of both reagents being important (Knock 1967).Alkylating agents exert cytotoxic effects by transferring alkyl groups to DNA, thereby damaging the DNA and interfering with DNA transcription and cell division. This class of drugs mainly works by three distinct mechanisms:-The attachment of alkyl groups to DNA bases prevents DNA synthesis and RNA transcription, and it results in the DNA being fragmented by repair enzymes in a process to replace the altered bases. -The two arms of mustard drugs can cross-link DNA strands. In this process, two bases are linked together. Bridges can be formed within a single molecule of...

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Stereoselective oxidation by thionyl chloride leading to the indeno[1,2-c]isoquinoline system

Cited by 75 publications

References 1 publication

Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells

Bisindenoisoquinoline Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA Intercalator and Topoisomerase Inhibitor with Antitumor Activity

DNA Damaging Drugs

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