Paclitaxel
[CAS# 33069-62-4]

Identification

• Classification: API >> Antineoplastic agents >> Natural source antineoplastic agents
• Name: Paclitaxel
• Synonyms: 7,11-Methano-5H-cyclodeca[3,4]benz[1,2-b]oxete benzenepropanoic acid deriv.; Taxal; Taxol A
• Molecular Formula: C₄₇H₅₁NO₁₄
• Molecular Weight: 853.92
• CAS Registry Number: 33069-62-4
• EC Number: 608-826-9
• SMILES: CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C

Properties

• Melting point: 213 °C (dec.) (Expl.)
• Solubility: DMSO: soluble 50 mg/mL, methanol: soluble 50 mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS08 Danger
• Risk Statements: H315-H317-H318-H334-H335-H340-H341-H360-H361-H372-H413
• Safety Statements: P203-P233-P260-P261-P264-P264+P265-P270-P271-P272-P273-P280-P284-P302+P352-P304+P340-P305+P354+P338-P317-P318-P319-P321-P332+P317-P333+P317-P342+P316-P362+P364-P403-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Serious eye damage	Eye Dam.	1	H318
Skin sensitization	Skin Sens.	1	H317
Reproductive toxicity	Repr.	2	H361
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Germ cell mutagenicity	Muta.	2	H341
Reproductive toxicity	Repr.	1B	H360
Respiratory sensitization	Resp. Sens.	1	H334
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Germ cell mutagenicity	Muta.	1B	H340
Reproductive toxicity	Repr.	1A	H360
Carcinogenicity	Carc.	2	H351
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Reproductive toxicity	Lact.	-	H362
Acute toxicity	Acute Tox.	3	H301
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H332
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	3	H311
Specific target organ toxicity - single exposure	STOT SE	2	H371
Carcinogenicity	Carc.	1B	H350

Discovery and Applications

Paclitaxel is a natural product originally isolated from the bark of the Pacific yew tree, Taxus brevifolia, discovered in the late 1960s during a large-scale screening program for anticancer agents. The compound is classified as a diterpenoid with a complex polycyclic structure, containing a taxane core, which is a fused ring system, and an ester side chain that is critical for its biological activity. The discovery of paclitaxel represented a major breakthrough in cancer chemotherapy due to its unique mechanism of action and potent anticancer properties.

Paclitaxel functions primarily as a microtubule-stabilizing agent. Unlike many other chemotherapeutic drugs that inhibit microtubule formation, paclitaxel binds to the beta-tubulin subunit of microtubules and promotes their assembly while preventing their disassembly. This stabilization disrupts the normal dynamic instability of microtubules, which is essential for mitotic spindle function during cell division. Consequently, paclitaxel arrests cells in the G2/M phase of the cell cycle, leading to apoptosis or programmed cell death in rapidly dividing cancer cells.

The unique mechanism of paclitaxel makes it effective against a variety of solid tumors, including ovarian, breast, lung, and pancreatic cancers. Its approval by regulatory agencies in the early 1990s marked an important advancement in oncology, providing a new treatment option for patients with difficult-to-treat cancers. The drug is used both as a single agent and in combination with other chemotherapeutics, enhancing its clinical efficacy.

Due to the scarcity of natural sources and the complexity of its structure, the total synthesis of paclitaxel is challenging and not economically viable for large-scale production. Consequently, semisynthetic methods have been developed, utilizing precursors such as 10-deacetylbaccatin III, which can be extracted from the needles of European yew species. These semisynthetic processes allow for more sustainable and scalable production of paclitaxel for medical use.

Over the years, various formulations of paclitaxel have been developed to improve its solubility, delivery, and reduce side effects. The original formulation used Cremophor EL, a polyethoxylated castor oil, as a solvent, which was associated with hypersensitivity reactions. Newer formulations, such as albumin-bound paclitaxel nanoparticles, have been developed to enhance drug delivery, reduce toxicity, and improve patient outcomes.

Paclitaxel’s impact extends beyond its clinical use; it has spurred extensive research into microtubule biology, drug resistance mechanisms, and the development of new taxane analogs and derivatives. Resistance to paclitaxel remains a significant clinical challenge, often arising from alterations in tubulin, efflux pump expression, and changes in cell death pathways. Addressing these issues has led to ongoing efforts in medicinal chemistry and molecular biology to design improved therapies.

In summary, paclitaxel is a landmark chemotherapeutic agent derived from natural sources with a unique microtubule-stabilizing mechanism. Its discovery revolutionized cancer treatment and continues to influence drug development and cancer biology research. The compound’s complex structure, potent activity, and challenges related to production and resistance have made it a central focus in pharmaceutical science and oncology.

References

1990. Taxol Content in Bark, Wood, Root, Leaf, Twig, and Seedling from Several Taxus Species. Journal of Natural Products, 53(6).
DOI: 10.1021/np50072a039

1998. Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells. Cancer Chemotherapy and Pharmacology, 41(6).
DOI: 10.1007/s002800050756

2000. Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel. Cancer Chemotherapy and Pharmacology, 46(4).
DOI: 10.1007/s002800000155