Synthesis and antiproliferative activity of derivatives of the phyllanthusmin class of arylnaphthalene lignan lactones

Abstract

A series of arylnaphthalene lignan lactones based on the structure of the phyllanthusmins, a class of potent natural products possessing diphyllin as the aglycone, has been synthesized and screened for activity against multiple cancer cell lines. SAR exploration was performed on both the carbohydrate and lactone moieties of this structural class. These studies have revealed the importance of functionalization of the carbohydrate hydroxy groups with both acetylated and methylated analogues showing increased potency relative to those with unsubstituted sugar moieties. In addition, the requirement for the presence and position of the C-ring lactone has been demonstrated through reduction and selective re-oxidation of the lactone ring. The most potent compound in this study displayed an IC value of 18 nM in an HT-29 assay with several others ranging from 50 to 200 nM. In an effort to elucidate their potential mechanism(s) of action, the DNA topoisomerase IIa inhibitory activity of the most potent compounds was examined based on previous reports of structurally similar compounds, but does not appear to contribute significantly to their antiproliferative effects.

Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes

“…Notably, when non-natural sugars are affixed to the aglycone core of phyllanthusmin, especially potent analogs have been identified (half maximal inhibitory concentration <10 nM). 73,74 In order to streamline our exploration of the structure-activity relationship for substitution of the aryl core, we pursued a C-H functionalization strategy to rapidly generate a library of medicinal analogs. To this end, we subjected Ac-phyllanthusmin D to our HCl-mediated protocol.…”

Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition

“…Prior to biological testing, purity was determined by HPLC (Supplemental Figure 2A for PHY25, 2B for PHY30, and 2C for PHY34). Briefly, diphyllin glycoside starting materials (β-D-glycosyl diphyllin, α-L-arabinosyl diphyllin, and β-D-galactosyl diphyllin) were prepared according to a recent publication (36). Following the selective tert -butyldimethylsilyl protection of β-D-glycosyl diphyllin, per-methylation was cleanly accomplished (37).…”

Design, synthesis, and evaluation of cytotoxic activities of arylnaphthalene lignans and aza‐analogs

“…Natural arylnaphthalene lignans and analogs [1,2] continue to interest pharmaceutical industries owing to their biological activities. [3,4] Among them, arylnaphthalene lactones, which are present in a lot of plants often associated with traditional medicine use, are known to exhibit remarkable biological properties, especially antiproliferative, [5][6][7][8][9][10] antiviral, [11] antiplatelet, [12,13] and for this are considered as promising candidates for the elaboration of new drugs. [14] Natural products or analogs included in this family are classified into two types (A or B) related to the regio-orientation of the lactone ring (Figure 1).…”

“…13 C NMR (101 MHz, DMSO d 6 ): δ = 171.1, 150.6, 149.9, 145.7, 130.5, 123.2, 121.9, 121.2, 115.0, 107.8, 100.6, 68.3, and 55.5 (×2). IR ν max (cm −1 ): 3237, 1726, 1618, 1599, 1489, 1425, 1348, 1231, 1202, 1151, 1030, 978, 866, and 759; HRMS (ESI): m/z calcd for C 14 H 13 O 5 [M+H] + 261.0757; found: 261.0753.4-Hydroxy-1,6,7-trimethoxy-2-naphthoic acid(5) To a solution of ethyl 4-hydroxy-6,7-dimethoxy-2-naphthoate 1 (3.0 g, 10.86 mmol) in a 1:1 acetonitrile/methanol mixture (200 ml) was added at room temperature in one portion PIDA (3.5 g, 10.86 mmol). After stirring at room temperature for 2 h, the resulting mixture was filtered and washed with ethyl acetate.…”