Synthesis and Biological Evaluation of Phorbol‐Resiniferatoxin (RTX) Hybrids

Appendino, Giovanni; Bertolino, Andrea; Minassi, Alberto; Annunziata, Rita; Szállaśi, A; Petrocellis, Luciano De; Marzo, Vincenzo Di

doi:10.1002/ejoc.200400122

Cited by 12 publications

(14 citation statements)

References 35 publications

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“…Spectroscopic data of compound 6a were identical to those described in the literature. 33 General Procedure for the Preparation of 12,13-Diacylphorbols 7a−9a. Phorbols 7a and 8a were prepared from 5a and phorbol 9a from 6a following the procedure described above for the synthesis of 3a and 4a.…”

Section: ■ Conclusionmentioning

confidence: 99%

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

et al. 2021

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A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC–HRMS screening of the latex of Euphorbia resinifera. Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFGα) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGFα release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGFα assay and at inducing neural progenitor cell proliferation in vitro, also leading to enhanced neurogenesis in vivo when administered intranasally to mice.

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Section: ■ Conclusionmentioning

confidence: 99%

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

et al. 2021

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“…4 -Phorbol is formed from phorbol by base-induced vinylogous retro-aldol epimerization, and its esters have long been used as negative reference for the PKC-related activity of their corresponding phorbol esters [91]. 4 -PDD interacts with the transmembrane segment of TRPV4 at a site distinct from that of EETs, and its affinity seems dependant from the nature of the ester groups [92].…”

Section: -Phorboldidecanoate (-Pdd 40)mentioning

confidence: 99%

The Role of Natural Products in the Ligand Deorphanization of TRP Channels

Appendino¹,

Minassi²,

Pagani³

et al. 2008

CPD

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The ligand deorphanization of TRP channels has a tremendous potential for biomedical and nutritional research, and this review highlights the role that natural products have played in the identification of ligands for these targets and their establishment as viable candidates for drug discovery. Specific ligands have so far been discovered only for some thermoTRPs, like TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1, and the lack of selective pharmacology has been a major drawback for unraveling the biological role of TRPs. While genetic approaches (transgenic animal models) have partially compensate for the lack of ligands, the universal expression of TRPs in living systems and the success achieved with TRPV1 suggest that a systematic investigation of the natural products pool might alleviate this shortage, fostering adoption by small molecules within this class of still largely orphan biological targets.

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“…Instead they possess a high affinity for the vanilloid transient receptor potential (TRP) cation channel subfamily V member 4 (i.e., TRPV4) . Esterification at O-20 in phorbol 12,13- O -diesters with homovanillic acid also confers an affinity for TRPV4 to the resulting triesters . However, masking of O-20 causes a loss of affinity for PKC .…”

mentioning

confidence: 99%

“…13 Esterification at O-20 in phorbol 12,13-O-diesters with homovanillic acid also confers an affinity for TRPV4 to the resulting triesters. 14 However, masking of O-20 causes a loss of affinity for PKC. 15 The PKC activation by some 20acylated phorbols may be explained by nonspecific interactions.…”

mentioning

confidence: 99%

Phorbol Rearrangements

2018

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An alternative procedure for isolation of 4β-phorbol from seeds of Croton tiglium has been developed, and an artifact containing a furan ring formed by rearrangement of 12,13,20- O-triacylated phorbol derivatives into (6b S,7 R,8 R,8a S)-2-(hydroxymethyl)-5,7,9,9-tetramethyl-3,7,8,9,9a,9b-hexahydrocyclopropa[3',4']benzo[1',2':3,4]cyclohepta[1,2- b]furan-6b,8,8a-triol (8a) has been characterized. A mechanism involving an oxidative rearrangement and a decarboxylation for formation of the artifact is proposed.

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Synthesis and Biological Evaluation of Phorbol‐Resiniferatoxin (RTX) Hybrids

Cited by 12 publications

References 35 publications

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

The Role of Natural Products in the Ligand Deorphanization of TRP Channels

Phorbol Rearrangements

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