Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents

Huang, Qingqing; Wang, Lei; Lü, Wei

doi:10.1016/j.ejmech.2013.01.058

Cited by 39 publications

(23 citation statements)

References 116 publications

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“…Main advantage of this new chemotype is a significant increase in stability of the lactone ring in vivo . The recent advances in ring E‐modified camptothecins have been reviewed by Huang et al .…”

Section: Camptothecin – a Long‐distance Run From Nature To Bench To Bmentioning

confidence: 99%

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Bracher

Tremmel

2016

Archiv der Pharmazie

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Natural products are a rich source of bioactive compounds, and numerous natural compounds have found application in cancer chemotherapy. However, unfavorable physicochemical properties often prevent the use of the original natural product as a drug. A prominent example is camptothecin from the Chinese tree Camptotheca acuminata, which shows extraordinary cytotoxic activity based on a specific molecular mode of action (inhibition of human topoisomerase I). Due to its extremely poor solubility, the original natural product cannot be used as a drug. The marketed drug topotecan was developed from this lead structure by semi-synthesis utilizing a Mannich aminomethylation as the crucial step. In this review, the long-distance run leading to this drug and further perspectives are summarized.

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Section: Camptothecin – a Long‐distance Run From Nature To Bench To Bmentioning

confidence: 99%

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Bracher

Tremmel

2016

Archiv der Pharmazie

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“…Camptothecin displays cell toxicity and is used as an antineoplastic agent, belonging to a class of topoisomerase inhibitors. This natural product is unstable at physiological conditions because of its lactone E-ring, being poorly soluble in aqueous solutions and with limited pharmacokinetic half-time [100]. Vast efforts have been made to develop analogs that address these drawbacks.…”

Section: Pxr As a Potential Target To Manage Drug-induced Liver Inmentioning

confidence: 99%

Pregnane X receptor and drug-induced liver injury

Wang

Chai

Brewer

et al. 2014

Expert Opinion on Drug Metabolism & Toxicology

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Introduction The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI. Areas covered This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development. Expert opinion Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapetic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI.

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“…When SN38 is hydrolyzed in the physiological environment (pH 7.4) or under basic conditions, the lactone ring is opened to yield a carboxylate form, making SN38 nonfunctional. 4,5 Research has highlighted that the lactone ring of SN38 is stable at pH #4.5 and hydrolyzes completely to the carboxylate form at pH 9.0. 6 The instability of SN38 in physiological circulation is a major hurdle in its development, as the therapeutic effect of SN38 is prevented by its conversion to the carboxylate form.…”

Section: Introductionmentioning

confidence: 99%

SN38-loaded <100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study

Fang

Chuang

et al. 2018

IJN

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BackgroundSN38 (7-ethyl-10-hydroxycamptothecin) is a camptothecin derivative acts against various tumors. However, SN38 is hydrolyzed in the physiological environment (pH 7.4), and this instability interferes with its potential therapeutic effect. Our objective was to investigate SN38-loaded liposomes to overcome the poor solubility of SN38 and its biodistribution, which further diminish its toxicity.Materials and methodsThe sub-100 nm targeted liposomes was employed to deliver SN-38 and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay.ResultsThe SN38-loaded targeted liposomes consisted of small (100.49 nm) spherical nanoparticles with negative charge (−37.93 mV) and high entrapment efficiency (92.47%). The release behavior of the SN38-loaded targeted liposomes was fitted with Higuchi kinetics (R2=0.9860). Free SN38 presented initial burst release. The IC50 for the SN38-loaded targeted liposomes (0.11 μM) was significantly lower than for the SN38 solution (0.37 μM) in the MCF7 cell line (P<0.01). Confocal laser scanning microscopy also confirmed highly efficient accumulation in the MCF7 cells. Pharmacokinetics demonstrated that the SN38-loaded targeted liposomes had a slightly increased half-life and mean residence time and decreased area under the concentration–time curve and maximum concentration. The results suggested that retention was achieved while the exposure of SN38 was significantly decreased. A noninvasive in vivo imaging system also showed that the targeted liposomes selectively targeted MCF7 tumors. In vivo toxicity data demonstrated that the decrease in platelets was significantly improved by SN38-loaded targeted liposomes, and diarrhea was not observed in BALB/c mice.ConclusionIn summary, SN38-loaded targeted liposomes could be a good candidate for application in human breast cancer.

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Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents

Cited by 39 publications

References 116 publications

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Pregnane X receptor and drug-induced liver injury

SN38-loaded <100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study

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Evolution in medicinal chemistry of E-ring-modified Camptothecin analogs as anticancer agents

Cited by 39 publications

References 116 publications

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Pregnane X receptor and drug-induced liver injury

SN38-loaded &lt;100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study

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SN38-loaded <100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study