477-47-4

Usage

Uses

Used in Optoelectronic Applications:
(-)PPP is used as a conjugating polymer for its water solubility and optoelectronic properties, making it suitable for a variety of applications in the optoelectronic industry.
Used in Insulin Growth Factor 1 Receptor Inhibition:
(-)PPP is used as an insulin growth factor 1 receptor inhibitor, specifically as an antineoplastic agent, to inhibit the growth of cancer cells by targeting the IGF1R.
Used in Picropodophyllotoxin Applications:
(-)PPP is used in conjunction with Picropodophyllotoxin, a potent and selective inhibitor of insulin-like growth factor 1 receptor (IGF1R), which is non-competitive with ATP. It displays antiproliferative activity in numerous tumor cell lines and exhibits antiangiogenic activity, making it useful in cancer treatment and prevention of intimal hyperplasia after vascular injury.

Biological Activity

Orally active insulin-like growth factor 1 receptor (IGF1R) inhibitor that exhibits no activity at the insulin receptor, FGFR, PDGFR or EGFR. Inhibits IGF1R autophosphorylation (IC 50 ~ 1 nM), increases the fraction of cells in the G 2 /M phase and upregulates apoptosis. Exhibits antiproliferative effects in multiple cancer cell lines (IC 50 = 0.05 - 15 μ M), and has anticancer and antineovascularization activity in vivo .

Biochem/physiol Actions

Picropodophyllotoxin (PPP), an epimer of podophyllotoxin (PPT), has been reported to target insulin-like growth factor-I receptor (IGF-IR) and mediate anticancer functions. However, a study in 2007, has reported that PPP can induce G2-M cell cycle arrest even in IGF-IR deficient cells. Hence, the role of PPP in IGF-IR-mediated anticancer functions is debatable.

References

1) Girnita et al. (2004), Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth; Cancer Res., 64 236 2) Girnita et al. (2006), The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of iveal melanoma cells; Clin. Cancer Res., 12 1383 3) Menu et al. (2007), Targeting the IGF-1R using picropodophyllin in therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival; Int. J. Cancer, 121 1857 4) Razuvaev et al. (2007), The cyclolignan picropodophyllin attenuates intimal hyperplasia after rat carotid balloon injury by blocking insulin-like growth factor-1 receptor signaling; J. Vasc. Surg., 46 108

Upstream product

• 64-17-5 ethanol 
• 4354-75-0 8-hydroxy-7-hydroxymethyl-5-(3,4,5-trimethoxy-phenyl)-5,6,7,8-tetrahydro-naphtho[2,3-d][1,3]dioxole-6-carboxylic acid 
• 186581-53-3 diazomethane 
• 112066-16-7 4'-O-demethylpicropodophyllotoxin 
• 77-78-1 dimethyl sulfate 
• 40505-27-9 4-demethylpodophyllotoxin 
• 4375-06-8 epipicropodophyllotoxin 
• 518-28-5 podofilox 
• 78216-05-4 picropodophyllic acid hydrazide 
• 477-48-5 (5aR,8aS,9R)-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione 
• 477-48-5 podophyllotoxone 
• 75-08-1 ethanethiol 
• 261158-29-6 (1R,2S,3R,4R)-4-O-(2-trimethylsilylethoxy)methylpicropodophyllin 
• 7647-01-0 hydrogenchloride 

Downstream Products

• 47789-93-5 O-(3-Carboxy-propionyl)-picropodophyllin 
• 38491-90-6 (5R,5aR,8aS,9R)-8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl acetate 
• 78215-98-2 benzoylpicropodophyllin 
• 37158-54-6 (5aS)-5c-(2-bromo-3,4,5-trimethoxy-phenyl)-9c-hydroxy-(5ar,8ac)-5,8,8a,9-tetrahydro-5aH-furo[3',4';6,7]naphtho[2,3-d][1,3]dioxol-6-one 
• 7470-99-7 2-(3,4,5-Trimethoxybenzoyl)-4,5-(methylenedioxy)benzoic Acid 
• 42123-13-7 7-(3,4,5-trimethoxy-phenyl)-7H-[1,3]dioxolo[4,5-f]isobenzofuran-5-one 
• 6258-41-9 5-(3,4,5-Trimethoxy-phenyl)-8H-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6-one 
• 4354-75-0 8-hydroxy-7-hydroxymethyl-5-(3,4,5-trimethoxy-phenyl)-5,6,7,8-tetrahydro-naphtho[2,3-d][1,3]dioxole-6-carboxylic acid 
• 344585-17-7 α-apopicropodophyllotoxin 
• 477-48-5 (5aR,8aS,9R)-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxole-5,8-dione 
• 245321-94-2 picropodophyllotoxin ethyl ether 
• 108448-52-8 (+)-4-O-(tert-butyldimethylsilyl)picropodophyllin 
• 98369-20-1 picropodophyllin homolactone 
• 155325-15-8 4β-azido-4-deoxypicropodophyllotoxin 

Relevant academic research and scientific papers

Catalytic Enantioselective Synthesis of (-)-Podophyllotoxin

The first catalytic enantioselective total synthesis of (-)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of se

Synthesis of Novel Oxime Sulfonate Derivatives of 2′(2′,6′)-(Di)chloropicropodophyllotoxins as Insecticidal Agents

To discover novel natural-product-based pesticidal agents, we prepared a series of oxime sulfonate derivatives of 2′(2′,6′)-(Di)chloropicropodophyllotoxins by structural modification of podophyllotoxin. Their structures were well-characterized by proton nuclear magnetic resonance (1H NMR), high-resolution mass spectrometry (HRMS), optical rotation, and melting point. Moreover, the key steric structure of compound 5f was unambiguously determined by single-crystal X-ray diffraction. Additionally, their insecticidal activity was evaluated at 1 mg/mL against the pre-third-instar larvae of oriental armyworm (Mythimna separata Walker), a typical lepidopteran pest. Among all derivatives, compounds 4c, 5c, and 5d exhibited more promising insecticidal activity, with the final mortality rates greater than 60%, when compared to their precursor podophyllotoxin and the positive control, toosendanin. It demonstrated that introduction of the chlorine atom at the C-2′ or C-2′,6′ position on the E ring of picropodophyllotoxin or oxime sulfonate derivatives of picropodophyllotoxin was important for the insecticidal activity and introduction of a halogen (e.g., fluorine, chlorine, or bromine) atom-substituted phenylsulfonyl group on the oxime fragment of 2′(2′,6′)-(di)chloropicropodophyllones could lead to more promising compounds.

Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents

Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2′ position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1-C1′

NEW PROCESS FOR PREPARING CYCLOLIGNANS

The invention relates to a one-pot reaction for the preparation of a compound of Formula (I). The compound of Formula (I) may be further transformed into picropodophyllin and derivatives thereof.

Synthesis and quantitative structure-activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents

In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, 33 isoxazoline and oxime derivatives of podophyllotoxin modified in the C and D rings were synthesized and their structures were characterized by Proton nuclear magnetic resonance ( 1H NMR), high-resolution mass spectrometry (HRMS), electrospray ionization-mass spectrometry (ESI-MS), optical rotation, melting point (mp), and infrared (IR) spectroscopy. The stereochemical configurations of compounds 5e, 5f, and 9f were unambiguously determined by X-ray crystallography. Their insecticidal activity was evaluated against the pre-third-instar larvae of northern armyworm, Mythimna separata (Walker), in vivo. Compounds 5e, 9c, 11g, and 11h especially exhibited more promising insecticidal activity than toosendanin, a commercial botanical insecticide extracted from Melia azedarach. A genetic algorithm combined with multiple linear regression (GA-MLR) calculation is performed by the MOBY DIGS package. Five selected descriptors are as follows: one two-dimensional (2D) autocorrelation descriptor (GATS4e), one edge adjacency indice (EEig06x), one RDF descriptor (RDF080v), one three-dimensional (3D) MoRSE descriptor (Mor09v), and one atom-centered fragment (H-052) descriptor. Quantitative structure-activity relationship studies demonstrated that the insecticidal activity of these compounds was mainly influenced by many factors, such as electronic distribution, steric factors, etc. For this model, the standard deviation error in prediction (SDEP) is 0.0592, the correlation coefficient (R2) is 0.861, and the leave-one-out cross-validation correlation coefficient (Q2 loo) is 0.797.

Natural products-based insecticidal agents 6. Design, semisynthesis, and insecticidal activity of novel monomethyl phthalate derivatives of podophyllotoxin against Mythimna separata Walker in vivo

To discover the more potent analogs, 12 novel monomethyl phthalate derivatives of podophyllotoxin were synthesized and preliminarily tested against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. Compounds 8e-i showed the higher insecticidal activity than podophyllotoxin. Especially 8g exhibited the most potent insecticidal activity compared with toosendanin, a commercially available insecticide derived from Melia azedarach. The structure-activity relationships demonstrated that trans-lactone, 4β-substitution, 2β-chlorine substitution, and 4′-methoxy group were the important structural properties of podophyllotoxins for good insecticidal activity.

USE OF CYCLOLIGNANS FOR THE TREATMENT OF TYPE 2 DIABETES AND AS CONTRACEPTIVES

There is disclosed use of certain cyclolignans for prophylaxis or treatment of diabetes mellitus type 2, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeotic gl

Silenes in organic synthesis: A concise synthesis of (±)-epi- picropodophyllin

A concise, seven step synthesis of the aryl tetralin lignan lactone epi-picropodophyllin from piperonal is described. The key steps are a silene diene Diels-Alder reaction and the Hosomi-Sakurai reaction of the resultant silacyclohexene. The Royal Society

A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry.

A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picrop

Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (- )-picropodophyllin

Described is the first catalytic, asymmetric synthesis of (-)- podophyllotoxin and its C2-epimer, (-)picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogenmetal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate-(15) and maleate-IBF Diels- Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH4) of 16 provides meso diol 19, which is then treated with Ac2O, BzCl, and PhCH2COCl to provide the corresponding meso diesters, 20- 22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro- Michael ring opening to produce dihydronaphthalene 30, in which the C3 and C4 stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck- type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required α-stereochemistry at C1 is observed). The conjugate addition product is converted to (-)- picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)- podophyllotoxin, in three steps, through the introduction of a C2- epimerization step, under Kende conditions, prior to the final conjugate addition.