A New Class of Simplified Phorbol Ester Analogues:  Synthesis and Binding to PKC and ηPKC-C1B (ηPKC-CRD2)

Abstract

[formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.

Protein Kinase C Translocation by Modified Phorbol Esters with Functionalized Lipophilic Regions

“…Possible phorbol 20-OH protecting groups include simple aliphatic esters, 28,29 triphenylmethyl ethers, 30 and silyl ethers. 31 We first employed phorbol 20-(p-methoxy)trityl ether as a starting material because it is commercially available (albeit very expensive) and the mono(p-methoxy)trityl (MMTr) protecting group is easily removed in 80% acetic acid. 32 Since several of the phorbol ester derivatives in this study contain free carboxylic acids, concentration often resulted in the intermolecular removal of the MMTr group (see Supporting Information).…”

“…To selectively acylate the C12 or C13 hydroxyls, the primary allylic alcohol at C20 must first be protected. Possible phorbol 20-OH protecting groups include simple aliphatic esters, , triphenylmethyl ethers, and silyl ethers . We first employed phorbol 20-( p -methoxy)trityl ether as a starting material because it is commercially available (albeit very expensive) and the mono( p -methoxy)trityl (MMTr) protecting group is easily removed in 80% acetic acid .…”

En Route to D-Ring Inverted Phorbol Esters

“…Given the biological potency displayed by phorbol esters, substantial effort has been invested in mapping the phorbol ester pharmacophore and labeling phorbol esters to gain further understanding regarding the structural features of various PKC isoforms. , Beyond the construction of biological probes, however, many attempts at the tigliane skeleton have been undertaken, − along with total syntheses of phorbol − and related systems (e.g., resiniferatoxin and crotophorbolone), albeit the latter requiring considerable synthetic creativity. That said, biological evaluation of synthetic fragments and advanced intermediates is sparsely reported. , …”

“…That said, biological evaluation of synthetic fragments and advanced intermediates is sparsely reported. 21,22 Although, it is known that certain stereochemical changes on the periphery of the tigliane skeleton (e.g., C12 23 and C4 24 ) result in significant changes in potency, little is understood regarding the impact arising from more profound skeletal modifications. Conceptually, this approach is challenging as prior full skeletal syntheses were focused on total synthesis (i.e., constructing the entire skeleton and associated stereochemistry), whereas here a stereochemical and functional group flexible synthesis is required to gain access to nonnatural derivatives (e.g., 4), albeit templated from naturally occurring phorbol esters (e.g., 5) (Scheme 1).…”

Συμβολή Στη Χημεία Των Φωσφινικών Ψευδοπεπτιδίων Για Την Ανάπτυξη Ισχυρών Και Εκλεκτικών Αναστολέων Μεταλλοπρωτεασών Ψευδαργύρου

“…[171] Ο πιθανός μετασχηματισμός της αλδεΰδης 87 στην αντίστοιχη ημιαμινάλη, εξαιτίας της πιθανής προσβολής της αλδεϋδομάδας από την δ-αμιδομάδα, στις συνθήκες της αντίδρασης Horner-Emmons, δημιούργησε αρχικά κάποιες επιφυλάξεις για την έκβαση της παραπάνω αντίδρασης, παρόλο που σύμφωνα με βιβλιογραφικά δεδομένα, τα σταθεροποιημένα υλίδια αντιδρουν με ημιαμινάλες χωρίς προβλήματα. [172] Cbz Η χρησιμοποίηση συμπλόκων υδροφθορικής πυριδίνης [173] Η ανταγωνιστική σχάση του δεσμού μεταξύ θείου-οξυγόνου έναντι του δεσμού άνθρακαοξυγόνου κατά τις αντιδράσεις αναγωγής σουλφονικών εστέρων προς τα αντίστοιχα αλκάνια αποτελεί την πιο συνηθισμένη περιπλοκή των παραπάνω αντιδράσεων. [175] Το πρόβλημα αυτό, σε πολλές Το αντιδραστήριο λίθιο-τριαιθυλο-βορουδρίδιο (Super Hydride) αποτελεί αντιδραστήριο επιλογής για την αναγωγή σουλφονικών εστέρων προς τα αντίστοιχα αλκάνια σε περιπτώσεις που η αντίδραση περιπλέκεται από το σχηματισμό είτε της μητρικής αλκοόλης είτε του προϊόντος απόσπασης.…”