Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Abstract

Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of “latrunculin‐like” compounds, in which all characteristic structural elements of these macrolides were subject to pertinent molecular editing. Although all previously reported derivatives of 1 and 2 were essentially devoid of any actin‐binding capacity, the synthetic compounds presented herein remain fully functional. One of the designer molecules with a relaxed macrocyclic backbone, that is compound 44, even surpasses latrunculin B in its effect on actin while being much easier to prepare. This favorable result highlights the power of “diverted total synthesis” as compared to the much more widely practiced chemical modification of a given lead compound by conventional functional group interconversion. A computational study was carried out to rationalize the observed effects. The analysis of the structure of the binding site occupied by the individual ligands on the G‐actin host shows that latrunculin A and 44 both have similar hydrogen‐bond network strengths and present similar ligand distortion. In contrast, the H‐bond network is weaker for latrunculin B and the distortion of the ligand from its optimum geometry is larger. From this, one may expect that the binding ability follows the order 1 ≥ 44 > 2, which is in accord with the experimental data. Furthermore, the biological results provide detailed insights into structure/activity relationships characteristic for the latrunculin family. Thus, it is demonstrated that the highly conserved thiazolidinone ring of the natural products can be replaced by an oxazolidinone moiety, and that inversion of the configuration at C16 (latrunculin B numbering) is also well accommodated. From a purely chemical perspective, this study attests to the maturity of ring‐closing alkyne metathesis (RCAM) catalyzed by a molybdenum alkylidyne complex generated in situ, which constitutes a valuable tool for advanced organic synthesis and natural product chemistry.

Semisynthetic latrunculin B analogs: Studies of actin docking support a proposed mechanism for latrunculin bioactivity

“…Docking of latrunculins A and B has been reported recently by Fürstner, et al14 using AUTODOCK followed by optimization. Fürstner, et al used 1ESV,15 a complex of actin with latrunculin A (2.00 Å resolution), for their docking studies.…”

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

“…Our investigations along these lines are disclosed in the accompanying paper. [21,22] Experimental Section General methods: All reactions were carried out in flame-dried glassware under Ar. The solvents were purified by distillation over the drying agents indicated and were transferred under Ar: THF, Et 2 O (Mg/anthracene), CH 2 Where indicated, the signal assignments are unambiguous; the numbering Scheme is arbitrary and is shown in the inserts.…”

“…The analytical data of the synthetic sample are in excellent agreement with those of the natural product, including the chiroptical properties. [11] As will be outlined in the accompanying paper, [21] 3 effectively induces actin de-polymerization, although it is slightly less potent than its diastereomer latrunculin B (2).…”

“…[20] The accompanying paper in this issue outlines how digression from the underlying blueprint during a "diverted total synthesis" campaign provided for the first time important information about the basic structural requirements for actin binding. [21,22] The insights acquired were then translated into the design of a truncated latrunculin analogue of enhanced biological potency.…”

Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Latrunculins (Figure 1) are macrolides initially isolated from the marine sponge Negombata magnifica found in the red sea 10,13 and are known to bind to the G-actin monomer in a 1:1 complex blocking the ability of actin to polymerize into the growing filament. 14 …”