Synthesis and Antitumor Activity of 20(S)-Camptothecin Derivatives: A-Ring Modified and 7,10-Disubstituted Camptothecins.

Sawada, Seigo; Matsuoka, Sumiko; Nokata, Ken-ichiro; Nagata, Hiroshi; Furuta, Tomio; Yokokura, Teruo; Miyasaka, Tadashi

doi:10.1248/cpb.39.3183

Cited by 78 publications

(62 citation statements)

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“…63 Topotecan owes its increased solubility to a tertiary amine at the 9-position, while irinotecan presents solubilizing groups through the 10-hydroxyl moiety. Topotecan was the first topoisomerase I inhibitor approved for clinical trials by the US Food and Drug Administration following CPT.…”

Section: Camptothecin Modificationsmentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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This review summarizes the in vivo assessment--preliminary, preclinical, and clinical--of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and inactivity at physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity inhibiting DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or non-covalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.

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Section: Camptothecin Modificationsmentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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“…The camptothecin derivative, irinotecan (CPT-11), is a topoisomerase I inhibitor with single-agent activity against several human tumors including esophageal, gastric, and colorectal carcinomas (9)(10)(11)(12). SN-38, the active metabolite of irinotecan, binds to and stabilizes the topoisomerase I-DNA complex, preventing the religation of DNA during replication and transcription (13,14).…”

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A Phase II Trial of Irinotecan in Patients with Previously Untreated Advanced Esophageal and Gastric Adenocarcinoma

et al. 2005

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Chemotherapy options for esophagogastric adenocarcinoma remain limited. Irinotecan has demonstrated broad activity in a variety of epithelial malignancies. Forty-six patients with previously untreated, measurable, unresectable, or metastatic esophagogastric adenocarcinoma were enrolled. Patients received irinotecan (125 mg/m2 intravenously over 90 min weekly) for 4 consecutive weeks followed by a 2-week rest. Forty-three patients received at least one treatment and were evaluable for response and toxicity. One complete and five partial responses were observed, for an overall response rate of 14% (95% CI, 4-24%). Median survival for all 43 patients was 6.4 months (95% CI, 4.6-8.2 months). Grade 3 to 4 toxicity included 10 patients (23%) with neutropenia, 13 patients (30%) with late diarrhea, 6 patients (14%) with vomiting, and 6 patients (14%) with fatigue. We conclude that although single-agent irinotecan is an active agent for esophagogastric adenocarcinoma, the schedule utilized in this trial is associated with moderate toxicity. When used as a single-agent, a tri-weekly schedule may be preferable for this patient population.

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“…for C 16 H 17 NO 7 : C,57.31;H,5.11;N,4.18;O,33.40. Found: C,57.51;H,5.27;N,4.43;O,4,6,7,8,indolizine-5-carboxylate (26) and 3a- 3a,6,8,9,4,.…”

Section: Methodsmentioning

confidence: 99%

“…In the camptothecin series, structure-activity relationships are well established for modifications in rings A, B, D and E. They also indicate the necessity for a hydroxy lactone ring [6] and the capacity of substituents in positions 7, 9, 10 and 11 to maintain or improve biological activity. However contradictory results have been observed concerning the position 5, as hydroxy, methoxy or oxycarbonyl groups introduced in this position generally result in inactive products [7], while some 5-methylenecarbonyl substituents are tolerated and the inhibitory function is maintained [8] (Scheme 1).As part of a program focusing on potential anticancer agents [9], it was necessary to clarify the influence of an oxygenated substituent on position 5 of ring C. Our study began with the synthesis of camptothecin derivative 2, substituted by a carboxylic ester at position 5. Many total syntheses of camptothecin have already been published…”

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Studies on pyrrolidinones. Synthesis of new α‐pyridones derivatives

Malecki

Houssin

Héanichart

et al. 2003

Journal of Heterocyclic Chem

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Dimethyl 7-methoxycarbonylmethyl-5-oxo-1,2,3,5-tetrahydro-indolizine-3,8-dicarboxylate was synthesized starting from methyl pyroglutamate. A study was made of the reactions of this highly functionalized pyridone with ethyl iodide, selenium oxide, isoamyl nitrite and formaldehyde. Literature reports that reaction of 4-(1-carbomethoxypropyl)-5-carbomethoxy-1,6-cyclopentano-2-pyridone with formaldehyde lead to a 95% yield of a monolactone (26) precursor of camptothecin. Our experiments resulted in 15 % of this monolactone and 40% of a new dilactone (27).J. Heterocyclic Chem., 40, 45 (2003).The isolation and structure of camptothecin 1 were reported in 1966 by Wall [1]. Interest in this cytotoxic drug and its hemisynthetic analogs was stimulated when their mode of action was discovered. The cleavable complex between topoisomerase I and DNA is stabilized by camptothecin and collision of the replication fork with this reversible complex [2] leads to cell death by preventing DNA religation [3]. The crystal structure of the DNAtopoisomerase I -camptothecin complex was resolved and two models of camptothecin -DNA -topoisomerase I interaction were proposed [4].Irinotecan and topotecan have emerged from these studies and are used in cancer treatment [5]. In the camptothecin series, structure-activity relationships are well established for modifications in rings A, B, D and E. They also indicate the necessity for a hydroxy lactone ring [6] and the capacity of substituents in positions 7, 9, 10 and 11 to maintain or improve biological activity. However contradictory results have been observed concerning the position 5, as hydroxy, methoxy or oxycarbonyl groups introduced in this position generally result in inactive products [7], while some 5-methylenecarbonyl substituents are tolerated and the inhibitory function is maintained [8] (Scheme 1).As part of a program focusing on potential anticancer agents [9], it was necessary to clarify the influence of an oxygenated substituent on position 5 of ring C. Our study began with the synthesis of camptothecin derivative 2, substituted by a carboxylic ester at position 5. Many total syntheses of camptothecin have already been published[10] and our aim was to apply our knowledge of the chemistry of pyroglutamic acid [11a] and indolizines [11b-d] to the general approach of Danishefsky [12] reported in the retrosynthetic pathway of Scheme 2.Application of this strategy is dependent on the synthesis of pyridone 3, which should easily be converted into the camptothecin analog 2. Thus it was necessary to introduce a heteroatom such as oxygen or bromine into position 1 and a hydroxymethyl group into position 6 of pyridone 4 or of one of its precursors (Scheme 2).Synthesis of the new pyridone 9 was performed in the first part of this work, followed by a study of the chemical reactivity of heterocycles 4 and 9, with compound 3 as an ultimate target.Methyl pyroglutamate (5) [13] was reacted with dimethyl sulfate to give iminoether 6 [14]. Condensation of 6 with Meldrum's acid produced a good ...

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Synthesis and Antitumor Activity of 20(S)-Camptothecin Derivatives: A-Ring Modified and 7,10-Disubstituted Camptothecins.

Cited by 78 publications

References 1 publication

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

A Phase II Trial of Irinotecan in Patients with Previously Untreated Advanced Esophageal and Gastric Adenocarcinoma

Studies on pyrrolidinones. Synthesis of new α‐pyridones derivatives

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