Synthesis and Biological Evaluation of Subglutinol Analogs for Immunomodulatory Agents

Abstract

Autoimmune diseases are chronic inflammatory diseases associated with high morbidity and mortality. Treatment options for autoimmune diseases have increased over the past several decades, but they are, in general, limited in their clinical efficacy due to high toxicity and lack of selectivity. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects. To define the structural requirements of subglutinols for immunomodulatory activity and to provide guiding principles on future therapeutic development, we prepared and evaluated several subglutinol analogs for their immunomodulatory activities. Our efforts identified a subglutinol analog with reduced structural complexity as a potential lead compound for future autoimmune drug development. Our study will provide an important framework for the design of potent and nontoxic immunomodulating agents derived from subglutinols.

Proteomic Analysis of a Hypervirulent Mutant of the Insect-Pathogenic Fungus Metarhizium anisopliae Reveals Changes in Pathogenicity and Terpenoid Pathways

“…The metabolite analyses and the EthOAc extractions were performed using the method in detail as described previously ( 18 ). Subglutinols A, B, C, and analog 45 were identified as described previously ( 46 , 47 ). Standards for destruxins and other molecules were used as indicated (Sigma-Aldrich Company Ltd.).…”

Mutation of a prenyltransferase results in accumulation of subglutinols and destruxins and enhanced virulence in the insect pathogen, Metarhizium anisopliae

“…Subglutinols A, B and C were identified as described (Kato et al ., 2016). The subglutinol analogue 45 was identified as described (Park et al ., 2020). Destruxins and other compounds were identified using available standards (Sigma‐Aldrich Company).…”

“…At least 26 different destruxins have been isolated from Metarhizium sp., with both chemical and biological synthetic pathways described (Pedras et al ., 2002; Liu and Tzeng, 2012). Another set of SMs produced by Metarhizium are the subglutinols (Kato et al ., 2016; Park et al ., 2020). Subglutinols are α‐pyrone diterpenoids originally isolated from the Fusarium subglutinans , which forms an endophytic relationship with the thunder god/thunder duke vine (i.e.…”

“…(A) The subglutinol biosynthetic pathway (cited from Kato et al ., 2016). (B) Structures of subglutinols, analogue 45 (product of subglutinol pathway), and the destruxins (cited from Kato et al ., 2016; Park et al ., 2020). Fig.…”

Asperginols A and B, Diterpene Pyrones, from an Aspergillus sp. and the Structure Revision of Previously Reported Analogues

“…Fungal meroterpenoids are a well-known class of hybrid natural products that are the focus of multidisciplinary research investigations due to their architecture and biological activities. , The diterpene pyrones are a group of 68 fungal meroterpenoids that comprise a characteristic pyrone, originating from the polyketide pathway, connected to a diterpene moiety. They possess a range of biological activities, making them the target of various synthetic and biological studies. − A review of the chemistry and biology of diterpene pyrones was recently published, in which the known metabolites were classified into three main types based on their biogenesis . Additionally, a unified numbering system for those natural products bearing the diterpene pyrone scaffold was proposed .…”