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Review
. 2015 Aug;32(8):1183-206.
doi: 10.1039/c5np00014a.

Conformation-activity relationships of polyketide natural products

Erik M Larsen  1 , Matthew R Wilson, Richard E Taylor
Affiliations
Review

Conformation-activity relationships of polyketide natural products

Erik M Larsen et al. Nat Prod Rep. 2015 Aug.

Abstract

Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature's assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide's conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues.

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Figures

Figure 1
Figure 1
In addition to rings, structural features within polyketides control conformational preferences about individual single bonds or pairs of adjacent single bonds through minimization of steric, electronic, and electrostatic interactions as well as through hydrogen-bonding.
Figure 2
Figure 2
The potent polyketide natural product bryostatin 1 (1) and 12-myristate 13-acetate (PMA) 2.
Figure 3
Figure 3
Overlay of acetal 3 (blue) and bryostatin 1 (green) solution conformations showing the internal hydrogen bonding network.
Figure 4
Figure 4
Major solution conformer of salicylate analogue 4.
Figure 5
Figure 5
Keck’s analogues 5 and 6 and Krische’s bryostatin analogue 7.
Figure 6
Figure 6
Laulimalide 8, isolaulimalide 9 and 11-desmethyl laulimalide 10.
Figure 7
Figure 7
Overlay of 8 (yellow) and 10 (green) lowest-energy solution conformers.
Figure 8
Figure 8
Overlay of laulimalide’s major solution conformation (yellow) with its tubulin-bound conformation (purple).
Figure 9
Figure 9
The marine polyketide, (–)-exiguolide.
Figure 10
Figure 10
Exiguolide analogues, 15-desmethyl 12, 15,18-bis-desmethyl 13, and (16,17-Z)-exiguolide 14.
Figure 11
Figure 11
Conformational overlay of 11 (gray), 12 (orange), 13 (green), and 14 (blue).
Figure 12
Figure 12
The microtubule-stabilizing agent, discodermolide 15.
Figure 13
Figure 13
Discodermolide’s major solution conformation and conformational control elements.
Figure 14
Figure 14
Conformationally-simplified analogues of discodermolide.
Figure 15
Figure 15
Comparison of dictyostatin and discodermolide structures.
Figure 16
Figure 16
Overlay of s-trans structure (blue) with proposed bioactive conformation (green) and solid state structure of discodermolide (yellow).
Figure 17
Figure 17
Dictyostatin-discodermolide hybrid molecules.
Figure 18
Figure 18
The ansamycin natural products, trienomycins A-F.
Figure 19
Figure 19
Overlay of trienomycin 21 (green) and monoene A 22 (yellow) structures generated through SYBYL molecular modeling.
Figure 20
Figure 20
Monoene A 22 and E 23 analogues.
Figure 21
Figure 21
The spongistatin class of natural products.
Figure 22
Figure 22
Simplified spongistatin analogues designed by the Smith lab.
Figure 23
Figure 23
Retained ABEF conformational structure of spongistatin 1 (green).
Figure 24
Figure 24
The epothilone class of natural products.
Figure 25
Figure 25
Conformational analysis of the C1-C8 and C11-C15 regions within 29.
Figure 26
Figure 26
Conformational analysis of the C11-C15 region within the C14-Me epothilone analogues.
Figure 27
Figure 27
(E)-9,10-dehydroepothilone B 32 and its major solution conformation.
Figure 28
Figure 28
C3-deoxyepothilone 33 and 2,3-dehydroepothilone 34.
Figure 29
Figure 29
Overlay of the major solution conformation (green) and tubulin-bound conformation (orange) of 28.
Figure 30
Figure 30
The ansamycin natural product, geldanamycin.
Figure 31
Figure 31
Geldanamycin analogues and trans- to cis-amide equilibrium.
Figure 32
Figure 32
Overlay of solid-state 42 (orange) with protein-bound 35 (gray).
Figure 33
Figure 33
Peloruside A.
Figure 34
Figure 34
Overlay of peloruside major solution conformers A (blue) and B (green) in solution.
Figure 35
Figure 35
Spontaneous equilibration of pyran lactol 44 to open form 45.
Figure 36
Figure 36
Peloruside’s tubulin bound conformation (gray) overlaid with proposed Díaz bound conformation B (green).
Figure 37
Figure 37
Zampanolide 46 and dactylolide 47.
Figure 38
Figure 38
TR-NOESY derived bioactive conformation of dactylolide while bound to tubulin.
Figure 39
Figure 39
DISCON-derived solution conformations, major conformers A (blue) and B (gray) and minor conformer C (green).
Figure 40
Figure 40
Overlay of zampanolide co-crystal structure (green) bound to tubulin H229 (gray) with solution conformer A (blue).
Figure 41
Figure 41
Altmann’s dactylolide analogues, C13-desmethylene 48 and ether 49.
Scheme 1
Scheme 1
Representative transacetalization macrocyclic ring closure.
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