Synthesis and Anticancer Activity of Structure Simplified Naturally Inspired Dimeric Chromenone Derivatives

Abstract

Select dimeric chromenones exhibit low micromolar cytotoxicity toward lymphoma and leukemia cell lines, L5178Y and HL60, respectively. The bioactive dimeric chromenones were identified from a focused library of structurally simplified derivatives of naturally occurring dimeric chromenones and tetrahydroxanthones that was prepared as part of this study. The simple dimeric chromenone scaffolds contain no stereogenic centers, are easily synthesized, and may be utilized as lead compounds in cancer research and drug discovery.

Phomoxanthone A Targets ATP Synthase

“…There is little literature on the structure‐activity relationship of phomoxanthone A. The few reports available show that phomoxanthone A analogs containing various substitution patterns on the oxygen substituents can retain anticancer activity [3,8] . Based on these observations we decided to conjugate a minimalistic diazirine probe to the parent compound via an ether or ester linkage.…”

“…The few reports available show that phomoxanthone A analogs containing various substitution patterns on the oxygen substituents can retain anticancer activity. [3,8] Based on these observations we decided to conjugate a minimalistic diazirine probe to the parent compound via an ether or ester linkage. With this in mind, we prepared two known diazirine probes for our studies (3 a and 3 b Scheme 1).…”

“…Phomoxanthone A (1) is a naturally occurring dimeric tetrahydroxanthone that possesses both an enticing molecular architecture and impressive biological properties (Figure 1). [1][2][3][4][5][6][7][8][9][10] For example, phomoxanthone A is known to have antibacterial, antimalarial, and anticancer activity. It has been observed that 1 is equally as effective at killing both cisplatin sensitive and cisplatin resistant cancer cells.…”

“…The challenges associated with a total synthesis of 1 include the formation of difficult tertiary ether stereocenter (highlighted in purple). As we studied and advanced synthetic methods to enable the construction of phomoxanthone A and its structurally related analogs, [8,[11][12][13] we became more enamored with both its recognized anticancer properties and the emerging collection of evidence suggesting that 1 may affect cancer cells through a unique mechanism of action. A 2018 study from Bohler and coworkers found that phomoxanthone A (1) causes rapid disintegration of the inner mitochondrial membrane, but it did not identify the biomolecular targets.…”

A CommonC2‐Symmetric 2,2’‐Biphenol Building Block and its Application in the Synthesis of (+)‐di‐epi‐Gonytolide A

“…In a bidirectional manner, the biphenol building block was advanced to 5,5’‐dimethoxy‐ and 5,5’‐dihydroxy‐chromonecarboxylate‐8,8’‐dimers 28 and 26 . While these axially chiral natural product fragments and simplified derivatives thereof have been known since the 1960 s [45] and gained interest more recently, [46] the outlined work represents their first enantioselective synthesis. Starting from 26 , the so far unknown unsymmetrical chromanone lactone dimer (+)‐2’,11‐di‐ epi ‐gonytolide A 2 was synthesized.…”