10 research outputs found
Total Synthesis of (±)-Phomoidride D
Described herein is a synthetic strategy for the total synthesis of (±)‐phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI2‐mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion
Development of Potent and Selective Inhibitors of Aldo–Keto Reductase 1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase) Based on <i>N</i>-Phenyl-Aminobenzoates and Their Structure–Activity Relationships
Aldo–keto reductase 1C3 (AKR1C3; type 5 17β-hydroxysteroid
dehydrogenase) is overexpressed in castration resistant prostate cancer
(CRPC) and is implicated in the intratumoral biosynthesis of testosterone
and 5α-dihydrotestosterone. Selective AKR1C3 inhibitors are
required because compounds should not inhibit the highly related AKR1C1
and AKR1C2 isoforms which are involved in the inactivation of 5α-dihydrotestosterone.
NSAIDs, <i>N</i>-phenylanthranilates in particular, are
potent but nonselective AKR1C3 inhibitors. Using flufenamic acid,
2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound,
five classes of structural analogues were synthesized and evaluated
for AKR1C3 inhibitory potency and selectivity. Structure–activity
relationship (SAR) studies revealed that a <i>meta</i>-carboxylic
acid group relative to the amine conferred pronounced AKR1C3 selectivity
without loss of potency, while electron withdrawing groups on the
phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds
did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production
of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising
leads toward new therapeutics for CRPC
Wharton-Fragmentation-Based Approach to the Carbocyclic Core of the Phomoidrides
The carbocyclic core of the phomoidrides has been synthesized efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular Diels–Alder sequence, tandem radical cyclization, and a late-stage Wharton fragmentation of a densely functionalized isotwistane skeleton
Toward the Synthesis of Phomoidride D
An efficient and highly stereoselective approach toward
the phomoidride
family of natural products is described. The carbocyclic core structure
was assembled using a tandem phenolic oxidation/Diels–Alder
cycloaddition and a tandem 5-<i>exo</i>-<i>trig</i>/5-<i>exo</i>-<i>trig</i> radical cyclization
to deliver an isotwistane intermediate that, upon a late-stage xanthate-initiated
Grob fragmentation, furnishes the requisite bicyclo[4.3.1]decene
Toward the Synthesis of Phomoidride D
An efficient and highly stereoselective approach toward
the phomoidride
family of natural products is described. The carbocyclic core structure
was assembled using a tandem phenolic oxidation/Diels–Alder
cycloaddition and a tandem 5-<i>exo</i>-<i>trig</i>/5-<i>exo</i>-<i>trig</i> radical cyclization
to deliver an isotwistane intermediate that, upon a late-stage xanthate-initiated
Grob fragmentation, furnishes the requisite bicyclo[4.3.1]decene