title: Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity.
abstract: Collismycin A is a member of the 2,2'-bipyridyl family of natural products that shows cytotoxic activity. Structurally, it belongs to the hybrid polyketides-nonribosomal peptides. After the isolation and characterization of the collismycin A gene cluster, we have used the combination of two different approaches (insertional inactivation and biocatalysis) to increase structural diversity in this natural product class. Twelve collismycin analogs were generated with modifications in the second pyridine ring of collismycin A, thus potentially maintaining biologic activity. None of these analogs showed better cytotoxic activity than the parental collismycin. However, some analogs showed neuroprotective activity and one of them (collismycin H) showed better values for neuroprotection against oxidative stress in a zebrafish model than those of collismycin A. Interestingly, this analog also showed very poor cytotoxic activity, a feature very desirable for a neuroprotectant compound.
authors.affiliation: Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garcia
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Vior
authors.forename: Javier
authors.initials: J
authors.lastname: González-Sabín
authors.forename: Alfredo F
authors.initials: AF
authors.lastname: Braña
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
authors.forename: Francisco
authors.initials: F
authors.lastname: Moris
authors.forename: Carmen
authors.initials: C
authors.lastname: Méndez
authors.forename: José A
authors.initials: JA
authors.lastname: Salas
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005798:Genes, Bacterial; D005818:Genetic Engineering; D006801:Humans; D005810:Multigene Family; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; C089907:collismycin A; D015082:2,2'-Dipyridyl