Synthesis and Bioactivity of a Brasilicardin A Analogue Featuring a Simplified Core

Abstract

An analogue 2 of Brasilicardin A, 1 (BraA), a potent immunosuppressive and cytotoxic agent, was synthesized in which the natural tricyclic skeleton was replaced with a synthetically more accessible substituted tetrahydronaphthalene core. BraA, this analogue (BraL), and cyclosporine A were tested for their ability to inhibit the proliferation of human T cells upon CD3/CD28 activation. Although BraL did not impact T cell activation over the dose range tested, this study shows the inhibitory activity of BraA on human T cells for the first time.

Asymmetric Total Synthesis of Brasilicardins

“…Although the mechanism of the immunosuppressive action of 1 has not been clarified in detail, it has been suggested that it is induced by amino acid deprivation via the inhibition of the amino acid transporter system L. [4] Currently used immunosuppressive clinical agents such as tacrolimus and cyclosporin Aoften cause side effects such as nephrotoxicity and arterial hypertension;t herefore,ana lternative to them is desired. [5,6] However, further biological and pharmacological studies of 1 have not been conducted because of its limited availability from natural sources;t herefore,e fficient chemical syntheses of 1 and its derivatives and simplified analogues are required to aid further studies. [5,6] However, further biological and pharmacological studies of 1 have not been conducted because of its limited availability from natural sources;t herefore,e fficient chemical syntheses of 1 and its derivatives and simplified analogues are required to aid further studies.…”

“…[6][7][8][9] However,t heir complex and unique three-dimensional structure has hampered their chemical synthesis.D espite considerable synthetic efforts over the last twenty years,t he sole successful total synthesis was the de novo construction of 1 and 3 by Anada, Hashimoto,a nd co-workers in 2017, [10] which involved sequential functionalization of the Wieland-Miescher ketone derivative and aD iels-Alder reaction/reductive angular methylation sequence [7] (Scheme 1a). [6][7][8][9] However,t heir complex and unique three-dimensional structure has hampered their chemical synthesis.D espite considerable synthetic efforts over the last twenty years,t he sole successful total synthesis was the de novo construction of 1 and 3 by Anada, Hashimoto,a nd co-workers in 2017, [10] which involved sequential functionalization of the Wieland-Miescher ketone derivative and aD iels-Alder reaction/reductive angular methylation sequence [7] (Scheme 1a).…”

The Immunosuppressant Brasilicardin: Determination of the Biosynthetic Gene Cluster in the Heterologous Host Amycolatopsis japonicum

“…Furthermore, BraC and BraD can now be used as starting points for the synthesis of new brasilicardin congeners with better properties. This is of high relevance for the generation of new derivatives since chemical synthesis of the brasilicardin core structure was so far not possible …”

“…However, the development of this promising immunosuppressant as drug for medical use was so far hindered as N. terpenica IFM 0406 shows only a low production titer and is furthermore categorized as a biosafety‐level 2 organism. Besides, due to its complex stereochemistry total synthesis of brasilicardins could not be achieved; especially the synthesis of the anti‐syn‐anti‐perhydrophenanthrene skeleton made the synthesis of brasilicardin congeners to a yet unsolved task.…”

High-Quality Draft Genome Sequence of the Actinobacterium Nocardia terpenica IFM 0406, Producer of the Immunosuppressant Brasilicardins, Using Illumina and PacBio Technologies

“…Both of these facts make the fermentative production of brasilicardin A expensive and elaborate. Due to its complex stereochemistry, a total synthesis has not been achieved to date (11–13). Therefore, we want to overcome this hurdle by heterologous expression of the corresponding biosynthetic gene cluster (14) in a nonpathogenic producer strain.…”