101860-50-8Relevant articles and documents
Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B
Fuerstner, Alois,De Souza, Dominic,Turet, Laurent,Fenster, Michael D. B.,Parra-Rapado, Liliana,Wirtz, Conny,Mynott, Richard,Lehmann, Christian W.
, p. 115 - 134 (2007)
The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne-yne metathesis of suitable diyne or enyne-yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me2C6H 3)N]3Mo (37) as precatalyst activated in situ with CH 2Cl2, as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)3 W≡CMe3] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine. and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner-Wadsworth-Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C-C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography.
Structure-Activity Studies of Truncated Latrunculin Analogues with Antimalarial Activity
Varghese, Swapna,Rahmani, Rapha?l,Drew, Damien R.,Beeson, James G.,Baum, Jake,Smith, Brian J.,Baell, Jonathan B.
, p. 679 - 693 (2020/11/30)
Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.
Total synthesis of the latrunculins
Smith III, Amos B.,Leahy, James W.,Noda, Ichio,Remiszewski, Stacy W.,Liverton, Nigel J.,Zibuck, Regina
, p. 2995 - 3007 (2007/10/02)
The total syntheses of (+)-latrunculin A (1) and (+)-latrunculin B (2), two architecturally novel toxins isolated from the Red Sea sponge Latrunculia magnifica (Keller), have been achieved via highly convergent and stereocontrolled routes (longest linear sequences, 16 and 12 steps, respectively). Formal syntheses of scalemic latrunculins C (3) and M (5) also derive from the construction of 2. Central features of the unified synthetic strategy include the aldol reaction of aldehyde (-)-12 with methyl ketone (-)-13, a novel acid-catalyzed reorganization-equilibration of ortho ester (-)-11, and Mitsunobu macrolide cyclization.
