Semisynthesis of novel monacolin J derivatives: hypocholesterolemic and neuroprotective activities.
A fungal strain able to naturally accumulate large amounts of monacolin J was improved by N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis and genetic disruption of the lovF gene. Semisynthesis was then used to produce novel statins by attaching different side chains at the C8 hydroxyl residue. In vitro hypocholesterolemic and neuroprotection assays showed that one derivative (NST0037) had a very low 3-hydroxy-3-methylglutaryl CoA reductase IC(50) and high protection rate for oxidative-stress-induced neuron cell death.
Campoy
Sonia
S
BioIndustrial Division, Neuron BPh, Granada, Spain.
Sierra
Saleta
S
Suarez
Beatriz
B
Ramos
Maria C
MC
Velasco
Javier
J
Burgos
Javier S
JS
Adrio
Jose L
JL
D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000378:metabolism*; D005658:Fungi / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000378:metabolism*
D000924:Anticholesteremic Agents; D009153:Mutagens; D009281:Naphthalenes; D018696:Neuroprotective Agents; D008769:Methylnitronitrosoguanidine; D006903:Hydroxymethylglutaryl CoA Reductases; C045376:monacolin J