Stable Axially Chiral Isomers of Arylnaphthalene Lignan Glycosides with Antiviral Potential Discovered from Justicia procumbens

Abstract

Arylnaphthalene lignans (ANLs) were known to have axial chirality due to the biphenyl skeleton with hindered rotation at the single bond. However, the stable ANL atropisomers have not been isolated from nature until the present study. Phytochemical separation of the methanol extract of the stems and barks of Justicia procumbens led to the isolation of 11 ANL glycosides including four pairs of new atropisomers with stable confirmations at room temperature. Their structures were deduced from elucidation of the extensive spectral data, and their absolute configurations were determined by the circular dichroism, electronic circular dichroism, and X-ray methods as well as the total synthesis of one pair of the atropisomers. The ANL compounds were evaluated for their antiviral potential, and it was found that they displayed great antiviral activity discrepancy between a pair of atropisomers due to the geometric orientation. The 1′P-oriented atropisomers showed much more significant antiviral potency than their corresponding 1′M-oriented counterparts. The biological activity discrepancy caused by the axial chirality will not only inspire synthetic design of novel ANL atropisomers to enrich the structural diversity, but also provide important hints to direct the synthetic approaches toward the antiviral drug development of ANL compounds.

Axial Chirality and Antiviral Activity Evaluation of Arylnaphthalene Lignan Glycosides from Justicia procumbens

“…Its molecular formula was determined to be C 27 H 26 O 13 by analysis of the HR‐ESI‐MS (559.1474 [M+H] + , calcd 559.1446) and NMR data (Table 1). The prominent UV absorption pattern at λ max 201, 255 and 309 nm and IR absorption bands at 3434 (hydroxy group), 1743 (ester group) and 1627 cm −1 (conjugated carbonyl group) of 1 were shown to be similar to those of the ANLs described in the literature [7,8] . Compound 1 was revealed to have the same ANL aglycone core structure containing a 6′‐hydroxy group by comparing its NMR spectral data (Table 1) with those of justatropmer A [7] …”

“…Compound 3 was determined to have the molecular formula of C 29 H 28 O 13 based on the analysis of the HR‐ESI‐MS (565.1313 [M–CH 3 −CO+Na] + , calcd 565.1322) and NMR data (Table 2). The analysis of the 1D and 2D NMR spectral data revealed that 3 has a similar planar structure to the known ANL compound justicidinoside C [7] . Compound 3 differs from justicidinoside C only by the presence of an acetyloxy group substituted at C‐6′′ of the β ‐D‐glucose moiety in 3 , which were determined by the two extra carbon signals observed at δ C 20.78 and 172.62 in the 13 C NMR spectrum and the presence of the long‐range correlations from the methylene protons H 2 ‐6′′ [ δ H 4.237 (1H, dd, J =2.2, 11.9 Hz), 4.143 (1H, dd, J =6.9, 11.9 Hz)] and the methyl protons at δ H 2.086 to the carbon at δ C 172.62 in the HMBC spectrum (Figure 2).…”

“…While the CD spectrum of 1 demonstrated the positive Cotton absorptions at 211 (Δ ϵ 2.44), 228 (Δ ϵ 14.09) and 261 (Δ ϵ 5.87) nm and the negative CD Cotton absorptions at 245 (Δ ϵ −1.82), 274 (Δ ϵ −3.96) and 312 (Δ ϵ −4.96), the CD spectrum of 2 displayed a completely opposite cotton effect, which are similar to the CD spectral patterns observed between justatropmers A and B (Figure 3). [7] The absolute configurations of 1 and 2 are therefore determined as 1′ P (i. e. R ) and 1′ M (i. e. S ), respectively. The two compounds are thus identified to occur in the nature as another pair of stable ANL atropisomers existed in the plant of J. procumbens .…”

“…The existence of the room temperature stable atropisomers is due to the fact that the 6′‐OH or 6′‐glucose substitution groups can generate a hindrance energy that is greater than the energy needed for the free biphenyl axial rotation. The plausible biosynthetic pathway (see Figure S2) of those atropisomers were derived from the shikimic acid biosynthetic pathway originating from cinnamic acid [7] . Based on the biosynthetic pathway, we speculated that other stable ANLs having axial chirality could co‐exist in J. procumbens .…”

“…However, the naturally occurring stable atropisomers are rare. In our previous study, [7] we obtained several stable axially chiral atropisomers isolated from the methanol extract of Justicia procumbens . The existence of the room temperature stable atropisomers is due to the fact that the 6′‐OH or 6′‐glucose substitution groups can generate a hindrance energy that is greater than the energy needed for the free biphenyl axial rotation.…”