7689-03-4 Usage
Uses
Used in Anticancer Applications:
(+)-Camptothecin is used as an antineoplastic and antitumor agent for its potent topoisomerase I inhibitory activity. It binds irreversibly to the DNA-topoisomerase I complex, inducing DNA-strand breaks and inhibiting religation. This action leads to the prevention of DNA replication and transcription, ultimately resulting in cell death. (+)-Camptothecin has been found to be effective against various types of cancer, including colorectal, ovarian, and lung cancers.
Used in Drug Development:
(+)-Camptothecin serves as a precursor for the synthesis of 10-hydroxycamptothecine, which is a topoisomerase inhibitor. This makes it a valuable starting material for the development of new anticancer drugs with improved pharmacological properties and reduced side effects.
Used in Pharmaceutical Research:
As a potent inhibitor of topoisomerase I, (+)-Camptothecin is widely used in pharmaceutical research to study the mechanisms of DNA replication, transcription, and repair. It also aids in the development of novel drug delivery systems to enhance the bioavailability and therapeutic outcomes of camptothecin-based treatments.
History
In 1966, Wall M E et? al. from the United States isolated an alkaloid from
Camptotheca acuminata and defined its chemical structure. The in?vitro anticancer
tests revealed the anticancer activity of the tryptophan-terpene alkaloid, which is
known as camptothecin and received widely concern. In 1975, Corey et?al. first opened the door for the chiral synthesis of
camptothecin, but the reaction step was long and the yield rate was very low. It
was not until 1997 that Ciufolini et?al. developed a new method for the synthesis of
camptothecin by five steps, with a total yield rate up to 51%. The great breakthrough
in the chemical synthesis of camptothecin has made its extensive application
become a reality.Hydroxycamptothecin, as a camptothecin derivative with a hydroxyl group on
the tenth carbon atom, is widely used for the treatment of various cancers. In 1969,
researchers from Shanghai Institute of Materia Medica found that hydroxycamptothecin possessed potent anticancer activity and low toxicity. And this finding promoted the production and clinical application of hydroxycamptothecin, but its usage
was interrupted for technology and quality. In the 1980s, hydroxycamptothecin was reproduced for clinical application with an improvement in producing technology, and hydroxycamptothecin got its approval number in 1986 for clinical usage in
China. In the 1990s, the US Food and Drug Administration approved the clinical
application of topotecan and irinotecan, which played a significant role in the prevention and treatment of cancers.
Indications
It is mainly used in digestive tract tumors and has a good effect on gastric cancer,
rectal cancer, and colon cancer. Besides, it can improve the surgical resection of
advanced gastric cancer and also has some therapeutic effect on bladder cancer and
lung adenocarcinoma. Moreover, camptothecin can be used for treatment of
psoriasis, warts, acute and chronic leukemia, and hepatosplenomegaly caused by
schistosomiasis.
Biological Activity
Cytotoxic plant alkaloid with antitumor properties; prototypic DNA topoisomerase I inhibitor.
Biochem/physiol Actions
(S)-(+)-Camptothecin binds irreversibly to the DNA-topoisomerase I complex, inhibiting the reassociation of DNA after cleavage by topoisomerase I and traps the enzyme in a covalent linkage with DNA. The enzyme complex is ubiquinated and destroyed by the 26S proteasome, thus depleting cellular topoisomerase I. Blocks the cell cycle in S-phase at low does and induces apoptosis in a large number of normal and tumor cell lines by cell cycle-dependent and cell cycle-independent processes.
Pharmacology
The pharmacology of camptothecin was mainly manifested as antitumor activity.
Camptothecin specifically targeted topoisomerase I and exerted anticancer activity
by inhibiting the synthesis of DNA.?Camptothecin mainly influenced the S phase of
cell cycle and was considered as a specific inhibitor agent of cell cycle. The results
of animal experiments showed that camptothecin had some inhibitory effects on
leukemia, Yoshida sarcoma, and Ehrlich ascites carcinoma.Previous clinical trials showed that camptothecin and its analogs have therapeutic effects on bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, neural stromal tumor, lymphoreticulosis, lung cancer, leukemia, lymphoma,
melanoma, ovarian cancer, pancreatic cancer, pediatric cancer, prostate cancer, and
liver cancer.Injection of camptothecin (2.5?mg/ml, 5–10?mg/day) with a treatment course of
140?mg achieved effective rate of 44.8% and 38.3% for gastric cancer and colon
cancer, respectively. Hydroxycamptothecin can be used for the prevention and treatment of gastric, liver, head, and neck cancer and leukemia, and the effective rate is
44%. In addition, the dimethyl sulfoxide solution of camptothecin was also successfully used for treatment of psoriasis.
Anticancer Research
Camptothecin (CPT) is a monoterpene indole alkaloid which is isolatedfrom the Chinese plant, Camptotheca acuminata (Nyssaceae) (Wall et al. 1966).CPT is used in cancer treatment since it is a potent inhibitor of DNA topoisomeraseI, which leads to DNA damage and the apoptosis in cancer cells. Studies have shownthat CPT itself is not suitable for clinical application since it has low water solubilityand certain side effects; therefore, water-soluble CPT derivatives such as topotecan and irinotecan were synthesized and have been successfully used for thetreatment of ovarian, lung, and colorectal cancers, and CPT has been approved by theFood and Drug Administration (FDA) of the USA. Currently, topotecan and irinotecanare all synthesized from natural camptothecin which is mainly extracted fromCamptotheca acuminata (Beegum et al. 2007). Subsequently, CPT was also recognizedand extracted from other plant species such as Ervatamia heyneana (Gunasekeraet al. 1979), Melliodendron megacarpum (Arisawa et al. 1981), Nothapodytes foetida(Govindachari and Viswanathan 1972), and Ophiorrhiza species (Beegum et al.2007). However, the extraction of CPT from plants is limited because of low yields(about 1 mg/g dry weight) and scanty natural resources (Lopez-Meyer et al. 1994),and scientists have used biotechnological ways especially cell culture methods forthe production of CPT and its derivatives (Kai et al. 2015).
Anticancer Research
CPT is extracted from Camptotheca acuminata, also called Chinese ornamentaltree. Irinotecan and topotecan are semisynthetic derivatives of camptothecin, whichcan be used for the therapy of colorectal and ovarian and small cell lung carcinoma,respectively (Shoeb 2006). Camptothecin is a potent antitumor agent that targetstopoisomerase I (Desai et al. 2008). The synthetic derivatives of camptothecin[20-(S)-9-nitrocamptothecin and 20-(S)-camptothecin] have the antitumor effects inbreast, prostate, and melanoma cancers. CPT-11 is a new derivative that showsantitumor effects against metastatic colorectal cancer (Hosseini and Ghorbani2015). It selectively inhibits topoisomerase I which is involved in cleavage andreassembly of DNA (Balunas and Kinghorn 2005). Camptothecin inhibits thesynthesis of nucleic acid in L-120 cells and HeLa cells (Desai et al. 2008).
Anticancer Research
It has low watersolubility and sideeffects. Thus, usedfor clinical purposes.The chemicalmodification of itsderivatives (e.g.,topotecan andirinotecan) iscurrently used inchemotherapy.
Clinical Use
Because of the toxicity and side effects of camptothecin, the currently used agents
in clinical applications are camptothecin derivatives like topotecan, irinotecan, and
hydroxycamptothecin. Topotecan, a water-soluble camptothecin derivative developed by SmithKline Beecham, was approved by FDA in 1996 for the treatment of
ovarian cancer. As another water-soluble camptothecin derivative approved by FDA
in 1996, irinotecan was mainly used in the treatment of advanced colorectal cancer.
In addition, it was also shown to have obvious inhibitory effect on small cell lung
cancer and leukemia. Hydroxycamptothecin possesses a broad-spectrum antitumor activity and was clinically used for intravesical therapy of bladder cancer. In
addition, it has remarkable curative effect on colon cancer, breast cancer, gastric
cancer, and leukemia.
References
1) Hsiang et al. (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I.; J. Biol. Chem., 260 14873
2) Li et al. (2006) Review camptothecin: current perspectives; Curr. Med. Chem., 13 2021
Check Digit Verification of cas no
The CAS Registry Mumber 7689-03-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 7,6,8 and 9 respectively; the second part has 2 digits, 0 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 7689-03:
(6*7)+(5*6)+(4*8)+(3*9)+(2*0)+(1*3)=134
134 % 10 = 4
So 7689-03-4 is a valid CAS Registry Number.
InChI:InChI=1/C16H23N5O4/c22-6-10-12(23)13(24)16(25-10)21-8-19-11-14(17-7-18-15(11)21)20-9-4-2-1-3-5-9/h7-10,12-13,16,22-24H,1-6H2,(H,17,18,20)
7689-03-4Relevant articles and documents
Host–guest systems based on pH-sensitive acyclic cucurbit[n]urils for controlled release of camptothecin
Lin, Jieling,Yang, Lei,Liao, Xiali,Gao, Chuanzhu,Yang, Bo
, p. 159 - 168 (2019)
Stimuli-responsive drug delivery systems may provide an effective way to treat cancer as they can release cargoes regularly according to changes in the human microenvironment. In this work, we design and prepare acid-controlled release complexes of camptothecin with three pH-sensitive acyclic cucurbit[n]urils. The inclusion complexes have been characterized by 1H and 2D nuclear magnetic resonance, X-ray powder diffraction, and phase solubility diagram. Cells incubated with complexes have been analyzed by high-content analysis, and cytotoxicity tests have been completed by MTT assay. The results showed that complexes with different binding constants can release the drug substance in the physiological pH environment of cancer cells, maintain good anticancer activity, and have low cytotoxicity. This provides a strategy about targeted and responsive systems of CPT for clinical application.
A practical six-step synthesis of (S)-camptothecin
Comins, Daniel L.,Nolan, Jason M.
, p. 4255 - 4257 (2001)
(Matrix Presented) An asymmetric synthesis of (S)-camptothecin (1) has been accomplished in six steps starting from two commercially available heterocycles.
Synthetic studies on camptothecins. Part 1: An improved asymmetric total synthesis of (20S)-camptothecin
Zhang, Li-Peng,Baoa, Yong,Kuang, Yun-Yan,Chen, Fen-Er
, p. 2057 - 2061 (2008)
A six-step asymmetric total synthesis of (20S)-camptothecin (1) has been accomplished in 25% overall yield starting from the known pyridone 3. The key steps in this synthesis are the chemoselective Ni-catalyzed hydrogenation of 3-cyanopyridone 6 to 3-formylpyridone 7 in AcOH/pyridine/H2O and the Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N-sulfonyloxaziridine into (4′S)-tricyclic hydroxylactone 2.
Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives
Zheng, Chao,Li, Ming-Zong,You, Tian-Pa,Tang, Wei-Ping,Lou, Li-Guang
, p. 51 - 61 (2019)
A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.
Kinetic and thermodynamic characterization of camptothecin hydrolysis at physiological pH in the absence and presence of human serum albumin
Thakur, Rishi,Kunadharaju, Sasank,Savva, Michalakis
, p. 704 - 715 (2009)
To accurately derive the kinetic and thermodynamic parameters governing the hydrolysis of the lactone ring at physiological pH, a derivative spectrophotometric technique was used for the simultaneous estimation of lactone and carboxylate forms of camptoth
Kinetics and mechanisms of activation of α-amino acid ester prodrugs of camptothecins
Song, Lin,Bevins, Robert,Anderson, Bradley D.
, p. 4344 - 4355 (2006)
The α-amino acid ester prodrugs of the antitumor agent camptothecin and a more potent, lipophilic silatecan analogue, DB-67, have been shown by NMR spectroscopy and quantitative kinetic analyses to undergo quantitative conversion to their pharmacologically active lactones via a nonenzymatic mechanism that at pH 7.4 is favored over direct hydrolysis. The alternate pathway involves the reversible intramolecular nucleophilic amine attack at the camptothecin E-ring carbonyl to generate a lactam (I) followed by a second intramolecular reaction to produce a bicyclic hemiortho ester (I′). The intermediates were isolated and shown to exist in an apparent equilibrium dominated by the hemiortho ester in DMSO using NMR spectroscopy. The conversion of prodrugs of camptothecin or DB-67 containing either α-NH2 or α-NHCH3 and their corresponding hemiortho esters were monitored versus time in aqueous buffer (pH 3.0 and 7.4) at 37 °C, and the kinetic data were fit to a model based on the proposed mechanism. The results indicated that while the prodrugs are relatively stable at pH 3, facile lactone release occurs from both the prodrugs and their corresponding hemiortho ester intermediates under physiological conditions (pH 7.4). The glycinate esters and their hemiortho esters were found to be more cytotoxic than the JV-methylglycinates or their corresponding hemiortho ester intermediates in vitro using a human breast cancer cell line (MDA-MB-435S), consistent with their more rapid conversion to active lactone. The pH dependence of the nonenzymatic pathway for conversion of these α-amino acid ester prodrugs suggests that they may be useful for tumor-targeting via liposomes, as they can be stabilized in an acidic environment in the core of liposomes and readily convert to the active lactone following their intratumoral release.
Asymmetric syntheses of (+)-camptothecin and (+)-7-ethyl-10- methoxycamptothecin
Tagami, Keiko,Nakazawa, Norio,Sano, Shigeki,Nagao, Yoshimitsu
, p. 771 - 775 (2000)
Total syntheses of (+)-camptothecin (1a) and (+)-7-ethyl-10- methoxycamptothecin (1b) from racemic ethyl 1-ethoxycarbonyl-3-oxopyrrolidin- 2-ylacetate (7) were accomplished via asymmetric hydroxylation onto C20 of racemic 20-deoxycamptothecin derivatives (3a,b) employing a chiral Davis reagent, (2R, 8aS)-(+)-(camphorylsulfonyl)oxaziridine.
A CAMPTOTHECIN DERIVATIVE FROM NOTHAPODYTES FOETIDA
Aiyama, Ritsuo,Nagai, Hisako,Nokata, Kenichiro,Shinohara, Chigiru,Sawada, Seigo
, p. 3663 - 3664 (1988)
A novel comptothecin derivative was isolated from the wood of Nothapodytes foetida.Its structure was elucidated by spectral data as (20S)-18,19-dehydrocamptothecin.
Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy
Liu, Qian,Liu, Minjie,Huang, Guangxin,Chen, Fen-er
, p. 2647 - 2651 (2019)
An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.
Hydrogean Peroxide Inducible Acid-Activatable Prodrug for Targeted Cancer Treatment
Liu, Jun,Wang, Jinhua,Si, Shuang,Xu, Jinyi,Xue, Peng
, p. 3231 - 3235 (2021)
Because some of the potentially most useful boronic acids are inherently unstable in blood plasma and exhibit poor selective retention in tumours, 2-heterocyclic N-methyliminodiacetic acid (MIDA) boronates provide a stable, spacious and highly effective harbor for prodrug conjugates. Herein we report MIDA boronates in conjunction with naphthalene-based fluorophores as suitable compounds for tumour diagnosis by virtue of their remarkable specificity and uniform benchtop stability. The shielding group was found to be effective at imparting stability under physiological conditions (pH 7.4), with rapid release of the drug upon exposure to the acidic microenvironment of the tumor. This approach significantly enhanced the efficiency of drug release and was found to exhibit fewer side effects, thus indicating its great potential for precision therapeutics.
