ポドフィロトキシン
ポドフィロックス · コンジロックス · (5R)-5,8,8aβ,9-テトラヒドロ-9β-ヒドロキシ-5-(3,4,5-トリメトキシフェニル)フロ[3',4':6,7]ナフト[2,3-d]-1,3-ジオキソール-6(5aαH)-オン · ポドフィリン酸ラクトン · (-)-ポドフィロトキシン · (5R)-5β-(3,4,5-トリメトキシフェニル)-9β-ヒドロキシ-5,5aα,6,8,8aβ,9-ヘキサヒドロフロ[3',4':6,7]ナフト[2,3-d]-1,3-ジオキソール-6-オン · (5R)-5β-(3,4,5-トリメトキシフェニル)-7α-(ヒドロキシメチル)-8β-ヒドロキシ-5,6,7,8-テトラヒドロナフト[2,3-d]-1,3-ジオキソール-6β-カルボン酸6,7-ラクトン · (5R)-5,5aα,8aβ,9-テトラヒドロ-9β-ヒドロキシ-5β-(3,4,5-トリメトキシフェニル)フロ[3',4':6,7]ナフト[2,3-d]-1,3-ジオキソール-6(8H)-オン
識別子と物理属性
| CAS No. | 477-47-4 |
|---|---|
| 分子式 | C22H22O8 |
| 平均分子量 | 414.4 g/mol |
| 単同位体質量 | 414.13146766 g/mol |
| SMILES | COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC |
| InChIKey | YJGVMLPVUAXIQN-XVVDYKMHSA-N |
| PubChem CID | 10607 |
| ChEMBL | CHEMBL61 |
| ChEBI | CHEBI:50305 |
| EC No. | 208-250-4 |
| DTXSID | DTXSID3045645 |
| 現地名 | ポドフィロトキシン |
化学・物理的性質
| XLogP | 2 |
|---|---|
| 極性表面積 | 92.7 |
| 水素結合供与体数 | 1 |
| 水素結合受容体数 | 8 |
| 回転可能結合数 | 4 |
| 重原子数 | 30 |
| 形式電荷 | 0 |
| 複雑度 | 629 |
| LogP（分配係数） | 1.5log Kow = 2.01 |
| Color/Form | Solvated crystals |
| 溶解度 | 100Insoluble in ethyl ether, ligroinslightly soluble in watersoluble in acetone, benzenevery soluble in ethanol, chloroform.In water, 150 mg/L at 25 °C /Estimated/1.14e-01 g/LDMSO:15.0(Max Conc. mg/mL)36.2(Max Conc. mM) |
| 融点 | 228114-118 °C183 °CMP: 114-118 °C (effervescence)228 °C183-184 °C (lit.) |
| 蒸気圧 | 8.3X10-15 mm Hg at 25 °C /Estimated/ |
| Optical Rotation | Hygroscopic amorphos white flakes, mp = 152-154 °C. Specific optical rotation = -76.4 deg (c=0.576 in methanol)specific optical rotation = -117.0 deg (c=0.668 in pyridine) /Podophyllotoxin-beta-D-glucoside/Specific optical rotation = -132.7 deg @ 20 °C/D, chloroform, 2% |
| ヘンリー定数 | Henry's Law constant = 3.8X10-18 atm-cu m/mol at 25 °C /Estimated/ |
| Physical Description | Light-brown to greenish-yellow powderCommercial resin preparations contain 5-25% podophyllum. [INCHEM]Solid |
| Collision Cross Section | 198.37 Ų [M+Na]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]189.74 Ų [M+H]+ [CCS Type: TW199.47 Ų [M+K]+ [CCS Type: TW187.85 Ų [M+H-H2O]+ [CCS Type: TW190.1 Ų [M+H-H2O]+ [CCS Type: TW189.6 Ų [M+H]+ [CCS Type: TW |
| Other Experimental Properties | Several polymorphic modifications. After drying up: mp = 183.3-184.0 °C. Specific optical rotation = -132.7 deg @ 20 °C/D (chloroform). Solubility in water at 23 °C = 12- mg/L. Soluble in alcohol, chloroform, acetone, warm benzene, glacial acetic acid.MW: 414.40. Crystals from acetone. MP = 214 °C. Higher-melting modification from abs ethanol, mp 228 °C. Specific optical rotation = +9.4 deg (c=0.7 in chloroform). Solubility in water at 25 °C approx 100 mg/L. Fairly soluble in chloroform, hot ethanol, acetic acid, acetone, dilute causticless soluble in benzene ether, carbon tetrachloride, propylene glycol. /Picropodophyllin/Hydroxyl radical reaction rate constant = 2.2X10-10 cu cm/molecule-sec at 25 °C /Estimated/ |
| 比旋光度 | -110.7 º (c=1, CHCl3) |
| 沸点 | 453.31°C (rough estimate) |
| 密度 | 1.2649 (rough estimate) |
| 屈折率 | 1.4480 (estimate) |
| 貯蔵条件 | 2-8°C |
| pKa（酸解離定数） | 13.26±0.40(Predicted) |
| 外観・状態 | 粉 |
| 色 | ホワイトからオフホワイト |
| Merck | 13,7628 |
| BRN | 99163 |
| 安定性 | 非常に吸湿性 |
| InChIKey | YJGVMLPVUAXIQN-XVVDYKMHSA-N |
| SMILES | COc1cc(cc(OC)c1OC)[C@H]2C3C(COC3=O)[C@@H](O)c4cc5OCOc5cc24 |
| LogP（分配係数） | 2.010 |
| CAS データベース | 518-28-5(CAS DataBase Reference) |
化学的特性
off-white fine crystalline powder
安全性と法規制
| GHS 分類 | This chemical does not meet GHS hazard criteria for 2.2% (1 of 46) of reports.DangerH301 (93.5%): Toxic if swallowed [Danger Acute toxicity, oral]H310 (95.7%): Fatal in contact with skin [Danger Acute toxicity, dermal]H315 (97.8%): Causes skin irritation [Warning Skin corrosion/irritation]H319 (97.8%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]H335 (95.7%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposureRespiratory tract irritation]P261, P262, P264, P264+P265, P270, P271, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P316, P319, P321, P330, P332+P317, P337+P317, P361+P364, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 46 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Reported as not meeting GHS hazard criteria per 1 of 46 reports by companies.There are 7 notifications provided by 45 of 46 reports by companies with hazard statement code(s).Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| 規制情報 | Chemical: Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, [5R-(5.alpha.,5a.beta.,8a.alpha.,9.alpha.)]- |
| その他の安全情報 | IMAP assessments - Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, [5R-(5.alpha.,5a.beta.,8a.alpha.,9.alpha.)]-: Environment tier I assessmentIMAP assessments - Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, [5R-(5.alpha.,5a.beta.,8a.alpha.,9.alpha.)]-: Human health tier I assessment |
| 火災の可能性 | Podofilox topical gel is flammable and should be kept away from open flames. |
| 有害性の概要 | The main active constituent of the resin from the roots of may apple or mandrake (Podophyllum peltatum and P. emodi). It is a potent spindle poison, toxic if taken internally, and has been used as a cathartic. It is very irritating to skin and mucous membranes, has keratolytic actions, has been used to treat warts and keratoses, and may have antineoplastic properties, as do some of its congeners and derivatives. [ChemIDplus] |
用途
解説
C22H22O8(414.40)．ポドフィロトキシンは，メギ科Podophyllum peltatumなどの地下茎からβ-D-グルコシドとして得られる．融点114～118 ℃．[α]20D－132°(クロロホルム)．エタノールや有機溶媒に可溶，水に難溶．抗腫瘍作用を有するが，毒性が強く，皮膚に炎症を起こす．LD50 8.7 mg/kg(ラット，静注)．森北出版「化学辞典（第2版）
用途
ポドフィロトキシン（podophyllotoxin, PPT、ポドフィロックス）は、ポドフィルム属植物の根および根茎に含まれる毒性リグナンである。局所ゲル剤がコンジロックスの商品名で、一部のヒトパピローマウイルスが原因の外性器尖圭コンジローマの治療に用いられる。ポドフィロトキシンおよびその誘導体（エトポシド、テニポシド、エトポホス）は、瀉下薬、発疱薬、抗リウマチ薬、抗ウイルス薬、抗腫瘍剤と幅広く応用されている。これらの抗がん活性は精力的に研究されており、肺がん、リンパ腫、生殖器腫瘍などに対する治療に使用されている。
説明
Podophyllotoxin (2,3-butyl-4-aromatic naphthene) is isolated from guijiu(Podophyllum) . There are two species as the main source of podophyllotoxin, Podophyllum hexandrum Royle and Podophyllum peltatum .Although podophyllotoxin has significant antitumor and antiviral activities, it showed several toxicity and side effects. Podophyllotoxin derivatives, etoposide (VP-16-213), Etopophos, amino sugar etoposide (NK6l1), and teniposide (VM26), have been developed as anticancer drugs. They are used to treat small cell lung cancer, testicular cancer, acute leukemia, malignant lymphoma, etc. But podophyllotoxin derivatives are not free of toxicity. Besides the narrowing of the anticancer spectrum and low water solubility, these drugs could induce severe myelosuppression, gastrointestinal side effects, etc.Although the synthetic and biosynthetic pathways of podophyllotoxin have been elucidated, it is still the most effective, economic, and fast way to extract podophyllotoxin from the plant.
来歴
Podophyllotoxin was first found in the Podophyllum peltatum L.The first time to isolate podophyllotoxin from podophyllin was in 1880. In 1942, it was found that venereal warts could be effectively treated by application of podophyllin.Subsequently, podophyllotoxin was reported to inhibit the growth of the tumor through the inhibition of the microtubule formation. The chemical structure of podophyllotoxin was elucidated in 1951.In the 1960s, two main podophyllotoxin derivatives were synthesized, etoposide and teniposide (VM-26) . In 1983, etoposide was approved by FDA.Etoposide and teniposide are used in frontline cancer therapy against various cancer types, such as small cell lung cancer, testicular cancer, etc. In 1996, etoposide phosphate analog (Etopophos) was launched in America. Etopophos is the prodrug of etoposide and can be rapidly absorbed and completely converted to the parent compound invivo. In 1990, WHO recommended 0.5% podophyllotoxin as the first-line drug for the treatment of condyloma acuminatum. Podophyllotoxin creams and gels are nowadays widely used in clinical practice.
使用
Podophyllotoxin is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species. It binds to topoisomerase II during the late S and early G2 stage, blocking tubulin polymerization and, thus, inhibiting mitosis. In addition to being used as a cathartic, purgative, antiviral agent, vesicant, and antihelminthic, podophyllotoxin is the starting material for the semi-synthesis of the anti-cancer drugs etoposide , teniposide , and etopophos.
製法・合成法
純化方法
The toxin recrystallises form *C6H6 (with 0.5C6H6), EtOH/*C6H6, aqueous EtOH (with 1-1.5H2O, m 114-115o) and CH2Cl2/pentane. When dried at 100o/10mm it has m 183-184o. [UV: Stoll et al. Helv Chim Acta 37 1747 1954, IR: Schecler et al. J Org Chem 21 288 1956.] It is an inhibitor of microtubule assembly [Prasad et al. Biochemistry 25 739 1986]. [Beilstein 19/10 V 666.]