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Synonym name: Irinotecan Hydrochloride Trihydrate, 136572-09-3
Catalogue No.: BP0768
Cas No.: 100286-90-6
Formula: C33H39ClN4O6
Mol Weight: 623.147
Botanical Source:
Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.
For Reference Standard and R&D, Not for Human Use Directly.
Inquire for bulk scale.
Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃
114.2000
3.4032
1.8406
.0621
.6213
3.5768
Low
86.6259
3.6996
No
No
No
No
Yes
Yes
0.6
No
No
No
Yes
Irinotecan Hydrochloride (CAS No.: 100286-90-6) is a semi-synthetic topoisomerase I inhibitor widely used in clinical research for colon and rectal cancers. As an important anti-tumor drug, irinotecan induces cancer cell apoptosis by interfering with DNA replication and transcription processes, significantly improving survival rates for patients with advanced colorectal cancer. In recent years, with the development of molecular targeted therapy and precision medicine, the mechanism of action of irinotecan hydrochloride and its interactions with various molecular targets have received in-depth attention. This paper will systematically review the chemical structure, physicochemical properties, pharmacological activity, mechanism of action, druggability evaluation, and clinical application prospects of irinotecan hydrochloride, aiming to provide a theoretical basis and research approach for the pharmacology of natural products and the development of anticancer drugs.
Irinotecan hydrochloride is a water-soluble semi-synthetic derivative with the molecular formula C33H38N4O6· HCl, molecular weight 586.6890. Its chemical structure is based on the framework of the natural product camptothecin, with water-soluble groups introduced through chemical modification, improving the bioavailability of the drug. The structural features of irinotecan include a pyrrole-furan ring system and an indole ring, forming its unique topoisomerase I inhibitory active center. Its LogP value is 3.4032, indicating moderate lipid solubility that facilitates membrane penetration; the polar surface area (TPSA) is 114.2 Ų, reflecting its moderate polarity, which aids drug binding to target proteins. Erinotecan hydrochloride has relatively low water solubility (0.0621 mg/mL), but its hydrochloride form significantly improves solubility, which is beneficial for clinical administration. The low permeability of the blood-brain barrier suggests limited impact on the central nervous system. The hERG channel inhibition test was negative, indicating a low risk of cardiotoxicity. The Ames test result was 0.6, indicating low genotoxicity and good safety.
The parent compound of irinotecan, camptothecine, was originally isolated from Camptotheca acuminata, a plant native to southern China. Camptothecin is a natural compound with significant antitumor activity, but its poor water solubility and high toxicity limit clinical application. Erinotecan introduces hydrophilic groups at the C-10 position of the indole ring through semi-synthetic modification of camptothecine, thereby improving its water solubility and pharmacokinetic properties. Camptothecin is typically extracted using organic solvent extraction combined with column chromatography purification technology, while erinotecan is prepared through chemical synthesis to ensure drug purity and batch-to-batch consistency. In recent years, advances in biosynthesis and metabolic engineering technologies have provided new avenues for the production of camptothecin and its derivatives, especially showing promise in increasing yield and reducing costs.
As a topoisomerase I inhibitor, irinotecan hydrochloride mainly stabilizes the topoisomerase I-DNA complex, blocking the single-strand breakage repair process of DNA, resulting in double-strand DNA breaks and triggering cell cycle arrest and apoptosis. Erinotecan exhibits significant cytotoxicity across various tumor cell lines, especially showing high selectivity and potency against colon and rectal cancer cells. In vivo experiments show that erinotecan can significantly inhibit tumor growth and extend survival in animal models.
In addition, irinotecan demonstrates the ability to regulate multiple signaling pathways, including AMPK, STAT3, and MAPK1, which play key roles in tumor growth, metastasis, and drug resistance. By regulating BCL2 family proteins, erinotecan promotes tumor cell apoptosis. Its effect on ABC transporters (such as ABCB1) also helps overcome multidrug resistance and enhances the antitumor efficacy of drugs. Recent studies have also found that irinotecan may influence the tumor microenvironment by regulating the expression of inflammatory factors TNF and lipoxygenase ALOX5, thereby inhibiting tumor invasion and metastasis.
The core mechanism of action of erinotecan hydrochloride is inhibition of topoisomerase I (TOP1), an enzyme that regulates the DNA superhelix state by cleavage and relinking single strands during DNA replication and transcription. Irinotecan binds to the TOP1-DNA complex, blocking the enzyme's dissociation step, leading to DNA strand breakage and accumulation, which triggers apoptosis signals. This mechanism gives erinotecan high selectivity in rapidly proliferating tumor cells.
In addition to the TOP1, erinotecan also affects several key molecular targets:
AMPK (PRKAA1): As a cellular energy sensor, AMPK activation can inhibit the metabolic adaptation of tumor cells. Elinotecan interferes with tumor cells' energy metabolism by modulating the AMPK signaling pathway.
BCL2: Erinotecan downregulates the expression of the anti-apoptotic protein BCL2, promoting mitochondrial pathway-mediated apoptosis.
STAT3: Erinotecan inhibits STAT3 activation, blocking its role in tumor cell proliferation and immune evasion.
ABCB1: As a transporter protein associated with multidrug resistance, ABCB1 expression affects intracellular drug accumulation. Erinotecan enhances drug sensitivity by inhibiting ABCB1 function.
ALOX5: Lipidase 5 is involved in inflammatory responses and tumor microenvironment regulation; irinotecan regulates its expression to help suppress tumor invasiveness.
LCK, MAPK1, GSK3B, TNF: These signaling molecules are involved in cell proliferation, differentiation, and inflammatory responses. Erinotecan exerts its anti-tumor effects through multi-target regulation.
In summary, erinotecan enhances its antitumor activity and potential to overcome resistance through its multi-target and multi-pathway synergistic effects.
Druggability evaluation of erinotecan hydrochloride shows it has good pharmacokinetic characteristics. Although the molecular weight of 586.6890 is relatively large, its moderate lipid solubility (LogP 3.4032) and polar surface area (TPSA 114.2) give it good cell membrane permeability. Although water-soluble is low, the hydrochloride form significantly improves solubility, making it suitable for intravenous administration. The blood-brain barrier has low permeability, reducing the risk of central nervous system toxicity.
Pharmacokinetic studies show that irinotecan is hydrolyzed in the body by hepatic esterase into the active metabolite SN-38, which has much higher antitumor activity than the parent drug. SN-38 is metabolized via UDP-glucuronyltransferase (UGT1A1), and the UGT1A1 gene polymorphism significantly affects drug clearance and toxicity, making it an important basis for individualized medication. Elinotecan and its metabolites are mainly excreted through bile; dosage adjustments are needed in patients with liver dysfunction.
In terms of safety, erinotecan does not inhibit hERG channels, resulting in a lower risk of cardiotoxicity. Ames test results showed low genotoxicity, and common adverse reactions in clinical use include bone marrow suppression and gastrointestinal reactions, but overall tolerability is good.
As one of the core drugs in colorectal cancer chemotherapy, irinotecan hydrochloride has been widely used clinically and combined with other chemotherapy drugs (such as fluorouracil and oxaliplatin) to form the FOLFIRI regimen, significantly improving patient survival rates and quality of life. With the rise of molecular targeted therapy, the combined application of irinotecan with targeted drugs and immune checkpoint inhibitors has become a research hotspot, aiming to overcome resistance and enhance efficacy.
Future research directions include:
Personalized medication: Dosage adjustment based on the UGT1A1 genotype reduces toxic side effects and improves treatment safety.
New drug delivery systems: Development of delivery systems such as nanocarriers and liposomes to improve drug targeting and bioavailability.
Combination therapy strategies: Studies on synergistic effects with immunotherapy and targeted therapy to expand indications.
Research on resistance mechanisms: In-depth analysis of irisecan-related resistance signaling pathways provides targets for new drug development.
Biosynthesis and Green Preparation: Optimizing the production process of erinotecan using synthetic biology techniques to reduce costs and increase yield.
In summary, irinotecan hydrochloride holds an irreplaceable position in colorectal cancer treatment, with its multi-target mechanism of action and good druggability providing valuable experience and insights for anti-tumor drug development.
As a semi-synthetic topoisomerase I inhibitor based on the natural product camptothecine, erinotecan hydrochloride has become an important drug in colorectal cancer treatment due to its unique chemical structure and multi-target mechanism. Its excellent pharmacological activity and druggability have led to its widespread clinical application and continuously promoted the development of anti-tumor therapies. In the future, with advances in precision medicine and new drug delivery technologies, irinotecan hydrochloride is expected to unlock greater potential, improve patient outcomes, and promote innovation and breakthroughs in the field of natural product pharmacology.
Shenshuai
Wenjing
Hedandan
