Synthesis and Biological Investigation of Δ¹²-Prostaglandin J₃ (Δ¹²-PGJ₃) Analogues and Related Compounds

Abstract

A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure-activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

The Evolution and Impact of Total Synthesis on Chemistry, Biology and Medicine

“…63 – 65 ). Compound 63 was also tested in a mouse model at the NCI for its toxicity and was found to be tolerated up to 200 mg/kg per dose (athymic nude mice; intraperitoneally administered) . These results bode well for further optimization to potential preclinical candidates for in vivo efficacy studies and eventually perhaps clinical trials.…”

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12‐Prostaglandin J3

“…Nicolaou and co‐workers recently reported several strategies for the total syntheses of Δ 12 ‐PGJ 3 . These strategies were subsequently applied to the development of a series of even more potent analogues as potential clinical candidates for stem cell cancer treatment, making this an even more sought‐after target . We have previously used 1 to form the C12−C13 bond (prostaglandin numbering) in the syntheses of a variety of prostanoids through conjugate addition of a nucleophile to the electrophilic enal moiety (Scheme A).…”

“…In order to construct Δ 12 ‐PGJ 3, disconnection of the C12−C13 bond through an aldol/dehydration reaction sequence would require β‐boryl aldehyde 8 and enone 9 (Scheme B). This type of aldol/dehydration strategy was originally reported by Kobayashi and has subsequently been applied to the syntheses of Δ 12 ‐PGJ 3 3 , and other closely related prostaglandins . Boryl aldehyde 8 was selected as a masked hydroxy aldehyde equivalent because it can be easily prepared by catalytic enantioselective conjugate borylation, and subsequently unmasked later in the synthesis by stereospecific oxidation of the boronic ester.…”

“…[16] These strategies were subsequently applied to the development of as eries of even more potent analogues as potential clinicalc andidates for stem cell cancert reatment, making this an even more sought-after target. [17] We have previously used 1 to form the C12ÀC13 bond (prostaglandin numbering) in the syntheses of av ariety of prostanoids through conjugate addition of an ucleophile to the electrophilic enal moiety (Scheme 2A). We reasoned that, by transforminge nal 1 into enamide 7,i tw ould change the reactivity of the C12-position from electrophilic to nucleophilic,f urther broadening the utility of our key enal (Scheme 2A).…”

Ceramide‐Templated Macrolactams: Total Synthesis and Biological Evaluation of Macrocyclic α‐Galactosylceramide Analogues and their Aglycons

“…Macrocyclization of therapeutically interesting compounds has proven to beneficially effect the selectivity and activity, especially when applied to peptides and carbohydrates . However, there are also excellent cases of macrocyclizations of non‐peptide natural products, for example the microtubule‐stabilizing diterpenoid docetaxel and the antileukemic agent Δ 12 ‐prostaglandin J 3 . Additionally, completely artificial macrocycles based on acyclic lead structures have been reported abundantly …”