Podophyllotoxin

Catalog	BBC518285
CAS	518-28-5
Structure
Synonyms	(5R)-5,8,8aβ,9-Tetrahydro-9β-hydroxy-5-(3,4,5-trimethoxyphenyl)furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aαH)-one
IUPAC Name	(5R,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
Molecular Weight	414.41
Molecular Formula	C22H22O8
Canonical SMILES	COC1=CC(=CC(=C1OC)OC)[C@H]2[C@@H]3[C@H](COC3=O)[C@H](C4=CC5=C(C=C24)OCO5)O
InChI	InChI=1S/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19-,20-/m0/s1
InChI Key	YJGVMLPVUAXIQN-XVVDYKMHSA-N
Boiling Point	453.31 °C
Melting Point	183-184 °C (lit.)
Purity	98%
Density	1.26 g/ml
Appearance	White powder
pKa	13.26±0.40

Case Study

Synthesis of Indole Carboxylic Acid Esters of Podophyllotoxin as Antiproliferative Agents

Zhang, Lei, et al. Medicinal Chemistry Research 28 (2019): 81-94.

Podophyllotoxin (1), a naturally occurring cyclolignan isolated from Podophyllum peltatum and Podophyllum hexandrum, is known for its cathartic, antirheumatic, antiviral, pesticidal, and antitumor properties. Structure-activity relationship (SAR) studies have revealed that the C-4 position of podophyllotoxin can accommodate significant structural diversification, including aromatic and heterocyclic substituents. In this study, a series of podophyllotoxin derivatives with indole carboxylic acid fragments at the C-4 hydroxyl position were synthesized.
Procedure:
To a solution of podophyllotoxin (0.29 mmol, 1 eq) and the appropriate indole carboxylic acid (1.5 eq), 4-dimethylamino-pyridine (1.2 eq) was added in N,N-dimethylformamide (4 mL) at 0 °C. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2 eq) was introduced. The reaction mixture was stirred for 2-8 hours at room temperature under an argon atmosphere. After completion, the reaction was quenched with water, and the crude product was collected by vacuum filtration, washed with water, and dried under reduced pressure. The crude product was then purified by column chromatography (EtOAc/PE, 4:1) to obtain the pure indole carboxylic acid ester derivatives of podophyllotoxin.

Synthesis of Podophyllotoxin Derivatives with Piperazinyl-Cinnamic Amide Moieties

Zhang, Xin, et al. Bioorganic Chemistry 123 (2022): 105761.

Podophyllotoxin, a natural lignan isolated from the dried rhizomes and roots of various Podophyllum species, demonstrates potent activity in disrupting tubulin polymerization and inducing cancer cell apoptosis. Structure-activity relationship studies have shown that modifications at the 4-position are tolerated without compromising its biological activity. In this study, we designed and synthesized podophyllotoxin derivatives incorporating piperazinyl-cinnamic amide moieties at the 4-position.
Procedure:
To a solution of podophyllotoxin (828 mg, 2 mmol) and sodium iodide (900 mg, 6 mmol) in dry acetonitrile (100 mL), methyl sulfonic acid (576 mg, 6 mmol) was carefully added dropwise. The mixture was stirred at 0 °C for 1 hour, and the reaction was monitored by thin-layer chromatography to ensure complete conversion of the substrate. Following this, barium carbonate (1.18 g, 6 mmol) and triethylamine (606 mg, 6 mmol) were added to adjust the pH to the range of 7-8. Piperazine (190 mg, 2.2 mmol) was then introduced, and the reaction mixture was stirred at room temperature for an additional 12 hours. The reaction was quenched with water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the combined organic layers were washed with water, brine, and dried over Na₂SO₄. After the solvent was removed under reduced pressure, the crude product was purified by column chromatography, yielding the intermediate 5 in 56% yield.

Synthesis of Podophyllotoxin-Linked Bile Acid Derivatives

Cai, De-sheng, et al. Bioorganic Chemistry 128 (2022): 106066.

The broad cytotoxicity and poor selectivity of podophyllotoxin limit its clinical applications. To overcome these limitations, conjugating bile acids with podophyllotoxin may enhance its selectivity for liver cancer cells, thereby facilitating its clinical translation.
Procedure:
Podophyllotoxin (equiv.) and bile acids (1.1 equiv.) were dissolved in dry dichloromethane (DCM, 15 mL). To this solution, 4-dimethylaminopyridine (DMAP, 0.5 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 2.0 equiv.) were added. The mixture was stirred at room temperature for 4 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was diluted with 50 mL of CH₂Cl₂ and sequentially washed with distilled water (3 × 25 mL) and brine (20 mL each). The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was then purified by flash chromatography.