Novel C-ring analogues of 20( S )-camptothecin. Part 3: synthesis and their in vitro cytotoxicity of A-, B- and C-ring analogues

Subrahmanyam, D.; Sarma, Vedula M.; Venkateswarlu, A.; Sastry, T. V. R. S.; Srinivas, A.; Krishna, C. Vamsee; Deevi, Danvanthri S.; Kumar, Sadhukhan A.; Babu, Moses J.; Damodaran, Narayanan K.

doi:10.1016/s0960-894x(00)00005-6

Cited by 22 publications

(13 citation statements)

References 9 publications

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“…Unless otherwise stated, all NMR spectra were measured in CDCl 3 solutions and referenced to the CHCl 3 signal. All 1 H and 13 C shifts are given in ppm (s ) singlet; d ) doublet; t ) triplet; dd ) quadruplet; dt ) doublet of triplets, m ) multiplet; br s ) broad signal). Coupling constants J are given in Hz.…”

Section: Methodsmentioning

confidence: 99%

Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

et al. 2009

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The synthesis, biological activity, and molecular modeling studies of C-ring-modified camptothecins are reported. A general synthetic protocol, based on "C-5 camptothecin (C-5-CPT) enolate chemistry", allows one to obtain various C5-substituted analogues. All new compounds, obtained as 1:1 epimeric mixtures, were tested for their antiproliferative activity. Experimental data showed that all novel derivatives are less active than the reference compounds and that one of the two epimers is more active than the other. Molecular docking simulations were performed to achieve more insight into the interactions between the new C5-modified CPTs and Topo I. A good correlation was observed when the data of cytotoxicity and the values calculated for the free binding energy were combined.

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Section: Methodsmentioning

confidence: 99%

Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

et al. 2009

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“…You et al 46 reported a series of 7-cycloalkylcamptothecin derivatives (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). As shown in Table III, many of the compounds exhibited IC 50 values in the low moicromolar-to-nanomolar level and were up to 40-fold more potent than 3, the reference compound.…”

Section: A and B Ring Modified Cpt Derivativesmentioning

confidence: 99%

“…Compound 94 showed significantly better efficacy relative to 3 when dosed orally in three ectopic xenograft models, H460, HT29, and PC-3. 60 So far, few studies have featured C-ring synthetic modifications, probably because of the low anticancer activity observed with certain reported analogs, including 5-hydroxy-, 5-alkoxy-, 5-acyloxy-, 5-hydroxymethyl-, and 5-amino-substituted derivatives, [61][62][63] as well as contradictory studies on 5-substituted CPT derivatives. For example, 5-propionyl and 5-ethoxy derivatives bearing a hydroxy, methoxy, or fluoro group at the β-position showed good antitumor activity.…”

Section: And D Ring Modified Cpt Analogsmentioning

confidence: 99%

Perspectives on Biologically Active Camptothecin Derivatives

et al. 2015

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Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.

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“…DRF-1042, chemically 5-(2′-hydroxyethoxy)-20(S)-camptothecin ( Fig. 1), is a novel C-ring modified CPT analog (Subrahmanyam et al, 1999(Subrahmanyam et al, , 2000. The 5 position in the C-ring is a chiral center, resulting in DRF-1042 being a equal mixture of two diastereomeric forms (5S and 5R), both showing anticancer activity against variety of cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Quantitative determination of DRF‐1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics

Upreti

Mamidi

Katneni

et al. 2003

Biomedical Chromatography

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A simple and sensitive high-performance liquid chromatography (HPLC) method has been developed and validated for the determination of DRF-1042, a novel orally active camptothecin (CPT) analog, in human plasma. The sample preparation was a simple deproteinization with acidified methanol yielding almost 100% recovery of DRF-1042. An isocratic reverse-phase HPLC separation was developed on a Supelcosil-LC318 column (250 x 4.6 mm, 5 microm) with mobile phase consisting of 1% v/v triethylamine acetate, pH 5.5 and acetonitrile (80:20, v/v) at a fl ow rate of 1.0 mL/min. The eluate was monitored with a fluorescence detector set at excitation and emission wavelengths of 370 and 430 nm, respectively. The standard curves were linear (r(2) > 0.999) in the concentration ranges 5.0-2004 ng/mL. The lower limit of quantification (LLQ) of the assay was 5 ng/mL. The mean measured quality control (QC) concentrations (range 5 ng/mL to 40 microg/mL) deviated from the nominal concentrations in the range of -10.5-0.08 and -14.5-7.97%, inter- and intra-day, respectively. The inter- and intra-day precisions in the measurement of QC samples at four tested concentrations, were in the range 0.64-5.89% relative standard deviation (RSD) and 0.33-14.7% RSD, respectively. The method was found to be suitable for measurement of plasma concentrations above the calibration curve after serial dilutions. Stability of DRF-1042 was confirmed in a battery of studies, viz., on bench-top, in the auto-sampler, in the stock solutions, after four quick freeze-thaw cycles, up to one month at -20 degree C in human plasma and up to 2 months in the ex vivo samples. The method is simple, sensitive and reliable and has been successfully implemented to investigate the clinical pharmacokinetics of DRF-1042 in cancer patients in a phase I clinical trial.

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Novel C-ring analogues of 20( S )-camptothecin. Part 3: synthesis and their in vitro cytotoxicity of A-, B- and C-ring analogues

Cited by 22 publications

References 9 publications

Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

Semisynthesis, Biological Activity, and Molecular Modeling Studies of C-Ring-Modified Camptothecins

Perspectives on Biologically Active Camptothecin Derivatives

Quantitative determination of DRF‐1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics

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