108740-89-2

Usage

Natural origin

17-hydroxywortmannin is a semisynthetic derivative of wortmannin, a natural product.

Target inhibition

It acts as a potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling pathways.

Anti-tumor activity

17-hydroxywortmannin has been shown to exhibit anti-tumor activity.

Therapeutic applications

It has potential therapeutic applications in cancer treatment.

Cancer cell growth suppression

17-hydroxywortmannin can suppress the growth of cancer cells by inhibiting the PI3K/Akt/mTOR signaling pathway, which is commonly dysregulated in cancer.

Signaling pathway dysregulation

The PI3K/Akt/mTOR signaling pathway is often abnormally active in cancer cells, and 17-hydroxywortmannin targets this pathway to exert its anti-cancer effects.

Combination therapy

17-hydroxywortmannin has been investigated for its potential to enhance the efficacy of other anticancer drugs.

Novel anticancer agent

17-hydroxywortmannin shows promise as a novel anticancer agent.

Further development

It may have potential for further development in cancer therapy.

InChI:InChI=1/C23H26O8/c1-10(24)30-13-7-22(2)12(5-6-14(22)25)16-18(13)23(3)15(9-28-4)31-21(27)11-8-29-20(17(11)23)19(16)26/h8,12-15,25H,5-7,9H2,1-4H3

Upstream product

• 19545-26-7 wortmannin 
• 22614-34-2 9α,11α-epoxy-4-androstene-3,17-dione 
• 108-24-7 acetic anhydride 
• 182203-28-7 C₂₈H₂₈O₈ 
• 182203-26-5 C₃₀H₃₆O₈ 

Downstream Products

• 19545-26-7 wortmannin 
• 884539-95-1 (1E,4S,4aR,5R,6aS,7S)-1-{[[3-(dimethylamino)propyl](methyl)amino]methylene}-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate 

Relevant academic research and scientific papers

Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs

Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activity studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortmannin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17β- hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.

Enantioselective Total Synthesis of (+)-Wortmannin

A concise and enantioselective total synthesis of the potent PI3K inhibitor (+)-wortmannin is described. A Pd-catalyzed cascade reaction was first developed to connect a synthon derived from Hajos-Parrish ketone to a furan moiety. The subsequent Friedel-Crafts alkylation of the β-position of a furan ring to an epoxide was optimized to establish the C10 quaternary center. (+)-Wortmannin was eventually accomplished by transformations following a late-stage oxidation of the furan allylic position. Kinome profiling and in vitro enzymatic assays were performed on 17-β-hydroxy-wortmannin and an epoxide analogue.

Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models

Phosphoinositide 3-kinase (PI3K) is an important target for cancer chemotherapy due to the deregulation of its signaling pathway in a wide spectrum of human tumors. Wortmannin and its analogues are potent PI3K inhibitors whose therapeutic use has been impeded by inherent defects such as instability and toxicity. Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development.

ANALOGS OF 17-HYDROXYWORTMANNIN AS PI3K INHIBITORS

The present invention relates to compounds of Formula (I): wherein R1, R2, R3, and R8 are defined herein, useful as P13K inhibitors.

Water soluble wortmannin derivatives

This invention relates to soluble derivatives of wortmannin that utilizes water-soluble polymers as carriers for a drug and includes compounds having the structures as described within the specification.

The first chemical synthesis of wortmannin by starting from hydrocortisone

The first chemical synthesis of wortmannin, a potent and specific inhibitor of PI 3-kinases, was achieved by starting from commercially available and optically pure hydrocortisone.