Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

Bonandi, Elisa; Mori, Mattia; Infante, Paola; Basili, Irene; Calcaterra, Andrea; Catti, Federica; Botta, Bruno; Passarella, Daniele

doi:10.1002/chem.202100315

Cited by 7 publications

(6 citation statements)

References 55 publications

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“…Besides, in their central moieties, withaferin B contains octadecan-5-yl, whereas withaferin A contains octadec-4-en-3-one. Of note, withaferin A has been reported to be a potential anti-cancer molecule that can inhibit cell proliferation, cell migration, and cell invasion [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Similarly, withaferin B, bound to the FAM72A-UNG2 heterodimer, could possibly block FAM72A-UNG2 signaling pathways in cancer cells [ 26 , 29 ]; however, thus far, the biological and therapeutic properties of withaferin B remain unknown.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Senthil¹,

Pramanik

Ekambaram³

et al. 2021

Cancers

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Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2 to prevent mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic bond and initiating the base excision repair pathway, thus maintaining genome integrity. In the present study, we determined a specific FAM72A-UNG2 heterodimer protein interaction using molecular docking and dynamics. In addition, through in silico screening, we identified withaferin B as a molecule that can specifically prevent the FAM72A-UNG2 interaction by blocking its cell signaling pathways. Our results provide an excellent basis for possible therapeutic approaches in the clinical treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Senthil¹,

Pramanik

Ekambaram³

et al. 2021

Cancers

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“…The withanolides are naturally found steroidal lactones that impart a distinctive earthy odor and flavor to Ashwagandha (Sangwan et al, 2017). Withaferin A was the primary isolated member of this group in 1965 (Bonandi et al, 2021).…”

Section: Morphological Characteristics Distribution Chemical Composit...mentioning

confidence: 99%

Withania somnifera as a Phytoherbal Growth Promoter for Broiler Farming – A Review

Oliveira

Attia

Khafaga

et al. 2024

Annals of Animal Science

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Poultry production significantly contributes to bridging the food gap worldwide. Several nations have limited the usage of antibiotic growth promotors due to bacterial resistance to antibiotics and the occurrence of residual antibiotics in the edible tissues of birds. The world is now turning to using natural alternatives to increase poultry production as well as birds’ resistance to diseases. Withania somnifera (WS; family: Solanaceae) is a precious medicinal herb utilized in several countries due to its distinct chemical, medicinal, and physiological properties. This plant has antioxidant, anti-aging, antimicrobial, antitumor, hepatoprotective, cardioprotective, neuroprotective, immunomodulatory, antidiabetic, antistress, and growth-promoting activities. In poultry, the dietary inclusion of WS revealed a promising result in enhancing productive performance, increasing disease resistance, reducing stress effects, and maintaining the bird’s health. Thus, the current review highlights the morphological features, distribution, chemical structure, and pharmacological features of Withania somnifera as a growth promoter herb for farming broiler chickens.

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“…In 2021, the Passarella group proposed simplifying the structure to contain cyclic carbamates with the ultimate goal of synthesizing and evaluating compound 1 ( Figure 4 D) [ 103 ]. However, stereoisomers of this compound ultimately proved inactive against Hh signaling.…”

Section: Chemotherapies That Target Hedgehog Signalingmentioning

confidence: 99%

“…Two pathway intermediates, 13b ( Figure 4 E) and 14b ( Figure 4 F), successfully inhibited SMO with racemic IC 50 values of 7.4 µM and 13.0 µM, respectively. Enantioselective synthesis revealed that (+)-13b and (−)-14b were the more potent inhibitors with IC 50 values around 6 µM compared to their enantiomers at 11–16 µM [ 103 ]. While it is surprising that deprotection of 14b to yield compound 1 eliminates activity, the tert-butyl(chloro)diphenylsilane (TBDPS) protecting group is highly lipophilic and might significantly impact protein interaction.…”

Section: Chemotherapies That Target Hedgehog Signalingmentioning

confidence: 99%

Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models

Dukes

Meade

2022

Biomedicines

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Basal Cell Carcinoma (BCC) is the most commonly diagnosed cancer worldwide. While the survivability of BCC is high, many patients are excluded from clinically available treatments due to health risks or personal choice. Further, patients with advanced or metastatic disease have severely limited treatment options. The dysregulation of the Hedgehog (Hh) signaling cascade drives onset and progression of BCC. As such, the modulation of this pathway has driven advancements in BCC research. In this review, we focus firstly on inhibitors that target the Hh pathway as chemotherapeutics against BCC. Two therapies targeting Hh signaling have been made clinically available for BCC patients, but these treatments suffer from limited initial efficacy and a high rate of chemoresistant tumor recurrence. Herein, we describe more recent developments of chemical scaffolds that have been designed to hopefully improve upon the available therapeutics. We secondly discuss the history and recent efforts involving modulation of the Hh genome as a method of producing in vivo models of BCC for preclinical research. While there are many advancements left to be made towards improving patient outcomes with BCC, it is clear that targeting the Hh pathway will remain at the forefront of research efforts in designing more effective chemotherapeutics as well as relevant preclinical models.

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Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

Cited by 7 publications

References 55 publications

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Withania somnifera as a Phytoherbal Growth Promoter for Broiler Farming – A Review

Modulation of Hedgehog Signaling for the Treatment of Basal Cell Carcinoma and the Development of Preclinical Models

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