Abstract
Two biotinylated derivatives of the fungal metabolite galiellalactone (1) were synthesized in order to facilitate the investigation of the molecular mechanism of action of the galiellalactonoids. Galiellalactone is a STAT3-signaling inhibitor that inhibits growth in vitro as well as in vivo of prostate cancer cells expressing activated STAT3. To provide a suitable point of attachment for biotin, the 8-hydroxymethyl derivative (3) and its 7-phenyl analogue 4 were synthesized by a modified tandem Pd-catalysed carbonylation and intramolecular vinyl allene Diels-Alder procedure previously developed. The two primary alcohols obtained, 3 and 4, were coupled to biotin as the 6-aminohexanoic acid amide, activated as the acid chloride, yielding the derivatives 5 and 6.
Highlights
The protein STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor that is involved in different cellular processes
It has been proposed that 1 interferes directly with the binding of STAT3 to DNA by reacting with a thiol group of a cysteine in STAT3 that is located in a domain of STAT3 that is involved in the binding to DNA [4], no evidence supporting this molecular mechanism of action has yet been presented
8-hydroxymethyl-galiellalactone (3) as well as 8-hydroxymethyl-7-phenyl galiellalactone (4) was prepared by a modified tandem Pd-catalysed carbonylation and intramolecular vinyl allene Diels-Alder strategy previously developed for the synthesis of 4-epi-1 [8]. 3 and 4 were coupled with an ester bond to the 6-aminohexanoic acid amide of biotin, yielding the two desired compounds 5 and 6 (Figure 1)
Summary
The protein STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor that is involved in different cellular processes. We envisioned that a hydroxymethyl group in position 8 of 1 (see Figure 1) would allow us to attach a biotin group via a suitable linker so that the STAT3 inhibiting effect was retained To this end, 8-hydroxymethyl-galiellalactone (3) as well as 8-hydroxymethyl-7-phenyl galiellalactone (4) was prepared by a modified tandem Pd-catalysed carbonylation and intramolecular vinyl allene Diels-Alder strategy previously developed for the synthesis of 4-epi-1 [8]. 3 and 4 were coupled with an ester bond to the 6-aminohexanoic acid amide of biotin, yielding the two desired compounds 5 and 6 (Figure 1) Both enantiomers of galiellalactone (1) have been prepared [9] [10] and found to be an potent inhibitors of IL-6 mediated STAT3 signaling [7] [11], 3 and 4 were prepared as racemates while 5 and 6 were obtained as pairs of diastereomers. During our work with analogues of 1 [8], we had indications (unpublished results) that a substituent in position 7 was beneficial for the potency, and to investigate if a phenyl group at C-7 affects the STAT3 inhibiting effect of galiellalactone (1) the 7-phenyl analogue 2 was prepared and assayed
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