Camptothecin - CAS 7689-03-4

Camptothecin - CAS 7689-03-4 Catalog number: BADC-00044

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Camptothecin (CPT) is a potent DNA enzyme topoisomerase I (topo I) inhibitor with an IC50 and IC70 of 50 nM and 0.225 μM for breast cancer cell line MDA-MB-231. Camptothecin is extratced from the barks of Camptotheca acuminata Decne. It can be used in cosmetics material.

Category
ADCs Cytotoxin
Product Name
Camptothecin
CAS
7689-03-4
Catalog Number
BADC-00044
Molecular Formula
C20H16N2O4
Molecular Weight
348.35
Camptothecin

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Description
Camptothecin (CPT) is a potent DNA enzyme topoisomerase I (topo I) inhibitor with an IC50 and IC70 of 50 nM and 0.225 μM for breast cancer cell line MDA-MB-231. Camptothecin is extratced from the barks of Camptotheca acuminata Decne. It can be used in cosmetics material.
Synonyms
CPT
IUPAC Name
(19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione
Canonical SMILES
CCC1(C2=C(COC1=O)C(=O)N3CC4=CC5=CC=CC=C5N=C4C3=C2)O
InChI
InChI=1S/C20H16N2O4/c1-2-20(25)14-8-16-17-12(7-11-5-3-4-6-15(11)21-17)9-22(16)18(23)13(14)10-26-19(20)24/h3-8,25H,2,9-10H2,1H3/t20-/m0/s1
InChIKey
VSJKWCGYPAHWDS-FQEVSTJZSA-N
Density
1.5±0.1 g/cm3
Solubility
Soluble to 30 mg/ml (86 mm) in DMSO, not soluble in water
Melting Point
260 °C (dec.)(lit.)
Flash Point
411.6±32.9 °C
Index Of Refraction
1.746
LogP
1.60
PSA
81.42000
Vapour Pressure
0.0±2.7 mmHg at 25°C
Mechanism Of Action
Camptothecin binds to the topoisomerase I and DNA complex resulting in a ternary complex, stabilizing it and preventing DNA re-ligation and therefore causes DNA damage which results in apoptosis.
Pharmacology
Camptothecin demonstrated strong anticancer activity in preliminary clinical trials but also low solubility and adverse drug reaction. Camptothecin is believed to be a potent topoisomerase inhibitor that interferes with the essential function of topoisomerase in DNA replication.
Toxicity (LD50)
Acute oral toxicity (LD50) in mouse: 50.1 mg/kg.
In Vitro
[3H]BrCPT labeling of topoisomerase I is enhanced greatly by the presence of DNA; very little labeling of isolated topoisomerase I or isolated DNA occurrs. Even in the presence of DNA, [3H]BrCPT labeling of topoisomerase I is inhibited by camptothecin, suggesting that both CPT and BrCPT bind to the same site on the DNA-topoisomerase I binary complex. With increasing concentrations of camptothecin, closed circular pRR322 DNA (form I) is converted to nicked circular DNA (form 11). This apparent nicking activitv of camptothecin required DNA topoisomerase I.
Clinical Trial Information
NCT NumberCondition Or DiseasePhaseStart DateSponsorStatus
NCT03531827Metastatic Castration Resistant Prostate CancerPhase 22021-09-14National Cancer Institute (NCI)Active, not recruiting
NCT00249990Corpus UteriPhase 22010-01-07University of New MexicoCompleted
NCT00947739Advanced Solid TumorsPhase 12015-06-18New Mexico Cancer Care AllianceCompleted
NCT00277082Corpus Uteri2010-01-07University of New MexicoCompleted
NCT027699622021-11-17National Cancer Institute (NCI)Recruiting
Application
ADCs Cytotoxin
Appearance
Cryst.
Purity
>98%
Quantity
Milligrams-Grams-Kilograms
Quality Standard
Enterprise Standard
Shelf Life
≥12 months if stored properly
Shipping
Room temperature
Pictograms
Acute Toxic
Signal Word
Danger
Boiling Point
757.0±60.0 °C at 760 mmHg
1.10-Boronic acid substituted camptothecin as prodrug of SN-38.
Wang L1, Xie S2, Ma L1, Chen Y3, Lu W4. Eur J Med Chem. 2016 Mar 24;116:84-89. doi: 10.1016/j.ejmech.2016.03.063. [Epub ahead of print]
Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.
2.Strategies Targeting DNA Topoisomerase I in Cancer Chemotherapy: Camptothecins, Nanocarriers for Camptothecins, Organic Non-Camptothecin Compounds and Metal Complexes.
Gokduman K1. Curr Drug Targets. 2016 May 2. [Epub ahead of print]
Topoisomerase I (Topo I) is a nuclear enzyme engaged in adjustment of DNA topological structure during cell cycle by cleaving and reannealing one of the two strands of the DNA double helix. Inhibition of this enzyme results in DNA strand breaks, ultimately leads to apoptosis and cell death; additionally it is in raised level in solid tumors contrasted with healthy tissues. Consequently, Topo I has a great potential as a target for the treatment of tumors. Although significant anti-tumor activity of first Topo I inhibitor, camptothecin (CPT), was observed on colon, lung, ovarian, breast, liver, pancreas and stomach cancers, CPT and its clinical derivatives (topotecan and irinotecan) have several restrictions. In addition to their low water solubility and cell resistance to CPTs, lactone ring opening causes a reduction in cytotoxic activity and severe side effects in physiological conditions (pH: 7.4, 37oC). Although numerous efficient nano drug delivery systems were developed for CPT and its derivatives to compensate the handicaps of these compounds, none of them has been approved so far.
3.Oral delivery of camptothecin using cyclodextrin/poly(anhydride) nanoparticles.
Huarte J1, Espuelas S1, Lai Y2, He B2, Tang J3, Irache JM4. Int J Pharm. 2016 Apr 19;506(1-2):116-128. doi: 10.1016/j.ijpharm.2016.04.045. [Epub ahead of print]
Camptothecin (CPT), a molecule that shows powerful anticancer activity, is still not used in clinic due to its high hydrophobicity and poor active form's stability. In order to solve these drawbacks, the combination between poly(anhydride) nanoparticles and cyclodextrins was evaluated. CPT-loaded nanoparticles, prepared in the presence of 2-hydroxypropyl-β-cyclodextrin, (HPCD-NP) displayed a mean size close to 170nm and a payload of 50μg per mg (25 times higher than the one of the control nanoparticles). CPT was not released from nanoparticles under gastric conditions. However, under intestinal conditions, about 50% of the drug content was released as a burst, whereas the remained drug was released following a zero-order kinetic. Pharmacokinetic studies revealed that the CPT plasma levels, from orally administered nanoparticles, were high and sustained up to 48h. The CPT oral bioavailability was 7-fold higher than the value obtained with the control, whereas its clearance was significantly lower than for the aqueous suspension.
4.Design, Synthesis, and Biological Evaluation of New Cathepsin B-Sensitive Camptothecin Nanoparticles Equipped with a Novel Multifuctional Linker.
Zhang X1,2, Tang K1, Wang H1, Liu Y1, Bao B1, Fang Y1, Zhang X1, Lu W1. Bioconjug Chem. 2016 Apr 21. [Epub ahead of print]
Traditional antitumor drugs such as camptothecin and paclitaxel derivatives are widely used in cancer chemotherapy. However, the major defects of those agents include severe toxicity and poor water solubility. With these in mind, a novel multifunctional linker was designed and two Cathepsin B (CTB) sensitive CPT conjugates (9a and 9b) were synthesized. Through click chemistry, additional functional group mPEG2000 can be easily introduced into these conjugates. The introduction of mPEG2000 fragment resulted in the formation of nanoparticles 1a and 1b (average particle sizes were 216.9 and 257.9 nm, respectively) with significantly increased water solubility (more than 19 000-fold). The release of therapeutic drug SN-38 in the presence of CTB was confirmed by HPLC and prodrug 1a showed potent in vitro cytotoxicity against all tested cell lines. Impressively, compared with irinotecan, CTB sensitive prodrug 1a displayed similar in vivo efficacy with remarkable decreased in vivo toxicity.

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