Synthesis and in vitro cytotoxicity of C(20)(RS)-camptothecin analogues modified at both B (or A) and E ring

Jew, Sang‐sup; Kim, Myoung Goo; Kim, Hee‐Jin; Rho, E.‐Y.; Park, Hyeung‐geun; Kim, Joon-Kyum; Han, Hyun-Jung; Lee, Heesoon

doi:10.1016/s0960-894x(98)00317-5

Cited by 21 publications

(8 citation statements)

References 9 publications

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“…1B), was developed by Chong Kun Dang Pharmaceutical Co. (Seoul, Korea). Belotecan currently is marketed in Korea as Camtobell \ for the treatment of ovarian and small cell lung cancers (7,8) based on a series of successful clinical trials (9).…”

mentioning

confidence: 99%

Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells

Jin

Kim

et al. 2008

Pharm Res

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confidence: 99%

Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells

Jin

Kim

et al. 2008

Pharm Res

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“…134 A full description of the complex SAR of CPT derivatives is beyond the scope of this review. A myriad of modifications to the core of 1 have been made, 105,[135][136][137][138][139][140][141][142][143] most of which were undertaken to improve solubility, lactone stability, or bioavailability. Briefly, the most active CPT derivatives generally have nitro or amino substituents at position 9, an unsubstituted 12-position, or a planar A-ring substituent such as ethylenedioxy or methylenedioxy, although there are exceptions.…”

Section: Semisynthetic Camptothecinsmentioning

confidence: 99%

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

Cinelli

2018

Medicinal Research Reviews

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Topoisomerases are DNA processing enzymes that relieve supercoiling (torsional strain) in DNA, are necessary for normal cellular division, and act by nicking (and then religating) DNA strands. Type 1B topoisomerase (Top1) is overexpressed in certain tumors, and the enzyme has been extensively investigated as a target for cancer chemotherapy. Various chemical agents can act as “poisons” of the enzyme’s religation step, leading to Top1‐DNA lesions, DNA breakage, and eventual cellular death. In this review, agents that poison Top1 (and have thus been investigated for their anticancer properties) are surveyed, including natural products (such as camptothecins and indolocarbazoles), semisynthetic camptothecin and luotonin derivatives, and synthetic compounds (such as benzonaphthyridines, aromathecins, and indenoisoquinolines), as well as targeted therapies and conjugates. Top1 has also been investigated as a therapeutic target in certain viral and parasitic infections, as well as autoimmune, inflammatory, and neurological disorders, and a summary of literature describing alternative indications is also provided. This review should provide both a reference for the medicinal chemist and potentially offer clues to aid in the development of new Top1 poisons.

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“…Substitution of the analogous 7-position of camptothecin with hydrogen bond donor–acceptor groups capable of increasing solubility improves biological activity over the parent compound 3,14,16,17. For indenoisoquinolines, groups such as amino, imidazole, morpholine, and N,N -dimethylamine, located on the lactam nitrogen at a distance of 2–3 methylene units from the aromatic core, confer superior top1 inhibition and antiproliferative activity 23,37.…”

Section: Introductionmentioning

confidence: 99%

“…Efforts to improve the solubility and potency of camptothecin ,– have provided 2 and 3 , ,,, the only FDA-approved top1 inhibitors for the treatment of cancer. Despite the clinical success of these compounds, camptothecin derivatives still suffer from poor solubility, reversibility of cleavage−complex formation, and dose-limiting toxicity. ,,, Another flaw of the camptothecins is in the E-ring lactone, which exists in equilibrium with its ring-open, hydroxycarboxylate form in vivo. , While the hydroxyacid form retains some of its potency, it possesses a high affinity for human serum albumin. , …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 14-Substituted Aromathecins as Topoisomerase I Inhibitors

et al. 2008

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The aromathecin or "rosettacin" class of topoisomerase I (top1) inhibitors is effectively a "composite" of the natural products camptothecin and luotonin A and the synthetic indenoisoquinolines. The aromathecins have aroused considerable interest following the isolation and total synthesis of 22-hydroxyacuminatine, a rare cytotoxic natural product containing the 12H-5,11a-diazadibenzo[b,h]fluoren-11-one system. We have developed two novel syntheses of this system and prepared a series of 14-substituted aromathecins as novel antiproliferative topoisomerase I poisons. These inhibitors are proposed to act via an intercalation and "poisoning" mechanism identical to camptothecin and the indenoisoquinolines. Many of these compounds possess greater antiproliferative activity and anti-top1 activity than the parent unsubstituted compound (rosettacin) and previously synthesized aromathecins, as well as greater top1 inhibitory activity than 22-hydroxyacuminatine. In addition to potentially aiding solubility and localization to the DNA-enzyme complex, nitrogenous substituents located at the 14-position of the aromathecin system have been proposed to project into the major groove of the top1-DNA complex and hydrogen bond to majorgroove amino acids, thereby stabilizing the ternary complex.

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Synthesis and in vitro cytotoxicity of C(20)(RS)-camptothecin analogues modified at both B (or A) and E ring

Cited by 21 publications

References 9 publications

Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells

Involvement of P-glycoprotein, Multidrug Resistance Protein 2 and Breast Cancer Resistance Protein in the Transport of Belotecan and Topotecan in Caco-2 and MDCKII Cells

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

Design, Synthesis, and Biological Evaluation of 14-Substituted Aromathecins as Topoisomerase I Inhibitors

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