Synthesis and biological evaluation of a potent salicylihalamide A lactam analogue

Abstract

The first synthesis of a lactam analogue of salicylihalamide A (1) is reported. A key step in the approach was a photochemical acylation coupling between amine 10 and dioxinone 9 to form the amide 19. Acetylation followed by RCM with Grubbs 1st generation catalyst gave the desired E-lactam 23 (E : Z ratio 87 : 13) as the major compound. Conversion of macrolactam 23 into the vinyl iodide 26 followed by Cu catalysed cross coupling with the diene amide 7 gave aza-salicylihalamide analogue 3 in good yield. This compound demonstrated potent activity against several human leukaemia cell lines.

Macrolactam analogues of macrolide natural products

“…8 The synthesis of the simplified 15-aza-salicylihalamide A analogue 2 shown in Scheme 5 involved the following key synthesis steps that are all scalable. 8 To form the amide, a photochemical acylation reaction 31 was utilised in which the quinoketene intermediate 35, formed from photolysis of 1,3-dioxanolone 34, was captured by the optically pure amine 36 to yield the diene 37 in 65% yield. This method of amide formation was far superior to alternatives involving traditional benzoic acid-amine cross couplings.…”

“…The 15-Aza-salicylihalamide A analogue 2 showed potent activity 8 against several leukemia cell lines and this was compared to the readily available V-ATP-ase inhibitor bafilomycin A1 (44) 33 since salicylihalamide (31) was not available (Figure 6). Analogue 2 was 10 times less active on average than bafilomycin A1 (44) but in a linear relationship, suggesting analogue 2 has the same mode of action.…”

Enantiospecific Synthesis and Cytotoxicity Evaluation of Oximidine II Analogues

“…The benzolactone class of natural products has attracted significant attention from both the synthetic and medicinal chemistry communities due to their unique architecture and their various bioactivities; particularly, their potent anticancer properties . Analogue studies have been aimed mainly at exploring the structure–activity relationships (SAR) for the enamide side chain, stemming from the known instability of the salicylihalamide side chain . The enamide could be hydrolyzed into the corresponding aldehyde and amide fragments in aqueous media and more importantly from a chemotherapeutic discovery perspective, be inactivated prior to reaching its intended target.…”

“…[13,17] The benzolactonec lass of naturalp roducts has attracted significant attentionf rom both the synthetic and medicinal chemistry communities due to their unique architecture and their various bioactivities;p articularly,t heir potent anticancer properties. [18,19] Analogue studies [20,21] have been aimed mainly at exploring the structure-activity relationships( SAR) for the enamide side chain,s temming from the known instability of Analogues of the anticancer naturalp roduct oximidine II were prepared and evaluated for cytotoxicity.O ne analogueo fo ximidine II that carries aC 15 allylic amide side chain as wella s two analogues with C15 vinyl sulfone side chains were found to lack cytotoxicity against the cancerc ell line SK-Mel-5, thereby confirming the necessity of the C15 enamide side chain of oximidine II for cytotoxicity.F our analogues, designed by com-parativem olecular similarity index analysis (CoMSIA), that feature al ess complex macrolactones caffold were prepared and tested. The two analogues carrying aC 15 vinyl sulfone group and the two analogues with aC 15 oximidineIIe namide side chain showed weak cytotoxicity against the SK-Mel-5 cell line and other cell lines, indicating that the designeds implified macrocycles cannotreplacethe oximidine II macrocycle.…”

“…3S,4S,5E,9E)-14-(tert-Butyldimethylsilyloxy)-3-(3-hydroxypropyl)-4-(methoxymethoxy)-3,4,7,8-tetrahydro-1H-benzo[c][1]oxacyclododecin-1-one(21).T oaflask containing macrocyclic diene 19 (404.6 mg, 0.6779 mmol) was added CH 2 Cl 2 (15.0 mL) and H 2 O (1.5 mL). The mixture was cooled to 0 8C, and DDQ (185.0 mg, 0.8149 mmol) was added in one portion.…”