Biosynthetic modularity rules in the bisintercalator family of antitumor compounds

Abstract

Diverse actinomycetes produce a family of structurally and biosynthetically related non-ribosomal peptide compounds which belong to the chromodepsipeptide family. These compounds act as bisintercalators into the DNA helix. They give rise to antitumor, antiparasitic, antibacterial and antiviral bioactivities. These compounds show a high degree of conserved modularity (chromophores, number and type of amino acids). This modularity and their high sequence similarities at the genetic level imply a common biosynthetic origin for these pathways. Here, we describe insights about rules governing this modular biosynthesis, taking advantage of the fact that nowadays five of these gene clusters have been made public (thiocoraline, triostin, SW-163 and echinomycin/quinomycin). This modularity has potential application for designing and producing novel genetic engineered derivatives, as well as for developing new chemical synthesis strategies. These would facilitate their clinical development.

Scheme 1

Chemical structures of triostin A and echinomycins/quinomycins A, B and C, showing the two different possibilities for intramolecular disulfide/thioacetal linkage.

Scheme 2

Chemical structures of luzopeptins A, B, C and quinoxapeptins A, B, C; where chromophores have been tailored to 6-methoxy derivatives.

Scheme 3

Chemical structures of thiocoraline and BE-22179, the only known two members containing a thiodepsipeptide structure.

Scheme 4

Chemical structures of sandramycin and quinaldopeptin, which belong to Major scaffold type (five amino acids in each half of the molecule).

Figure 1

Minor and Major scaffold types in bisintercalator compounds.

Scheme 5

Chemical structures of SW-163C, D, E, F and G, showing the two possibilities for disulfide bridge or thioacetal bond.

Figure 2

A hypothetical evolutionary tree on diversification of bisintercalators biosynthetic systems based on current known compounds.

Scheme 6

Biosynthetic steps towards 3HQA and QXCA.

Scheme 7

Biosynthesis of non-proteinogenic amino acids present in bisintercalator compounds.

Scheme 8

Tailoring modifications during the final steps of the biosynthesis of bisintercalators. (A) Methoxy group formation in chromophores; (B) Thioacetal bond formation; (C) Iterative alkylation in SW-163E, SW-163F and SW-163G.

Figure 3

Non-ribosomal peptide synthetase (NRPS) assembly line in bisintercalator natural compounds (thiocoraline version). L: Ligase domain, PCP: Peptidyl carrier protein domain, C: Condensation domain, A: Adenylation domain, E: Epimerization domain, M: Methyltransferase domain, TE: Thioesterase domain.

Figure 4

Cyclization carried out by thiocoraline thioesterase NRPS domain (TE) after the action of TioN S-methyltransferase (M₅). C: Condensation domain, A: Adenylation domain, PCP: Peptidyl carrier protein domain.