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    • Thus from this preliminary study

    2022-05-19

    Thus from this preliminary study, a working model of HIV-1 integrase was developed from which a selective inhibitor of the strand-transfer reaction displaying whole-cell activity and negligible cytotoxicity was produced. Compound 9 provides a promising scaffold for further elaboration, and current investigations include resolving a co-crystallised structure of 9 with the IN catalytic core in addition to further structure-based design iterations.
    Materials and methods
    Acknowledgments CPG was the recipient of an ARC DECRA fellowship (DE DE130100513) and acknowledges the postgraduate scholarship provided the University of Wollongong and the ARC Linkage program (LP0347088). ND acknowledges the University of Wollongong and Avexa for a matching scholarship.
    Introduction Dichrocephala benthamii C.B. Clarke, an annual herbaceous plant of the Asteraceae family, is distributed in China and India (Editorial Committee of Flora of China, 1977). This herb is used as a folk medicine among the Dai nationality of China for the treatment of indigestion, common cold, fever in children, pneumonia and hepatitis (Southern Yunnan Materia Medica, 2000). Previous studies from the petroleum ether fraction of this medicinal plant have yielded diverse secondary metabolites including four new sinapyl alcohol derivatives, and two unique and cytotoxic sesquiterpenoids dichrocephones A and B (Tian et al., 2013a, Tian et al., 2013b). In our ongoing mining of bioactive natural products from Traditional Chinese Medicine (TCM), we found that the EtOAc fraction of D. benthamii C.B. Clarke displayed strong inhibition against HIV-1 integrase. Based on this interesting find, further investigation resulted in isolation of five new clerodane diterpenoid dichrocephnoids A–E (1, 2, 6–8) together with three known analogues from the EtOAc fraction of D. benthamii C.B. Clarke (Fig. 1). This paper presents isolation, structural elucidation and biological evaluation of the isolated diterpenoids.
    Results and discussion The molecular formula of AG-14361 1 was established as C22H30O9 from the negative-ion HRESIMS at m/z 437.1820 [M–H]− (calcd 437.1812 for C22H29O9). The 1H NMR, 13C NMR (Table 1) and DEPT spectra revealed the presence of 22 carbons, consisting of two carboxyl moieties, two olefinic carbons, six methylene units (one oxygenated), six methine units (four oxygenated), one methyl groups, two methoxy groups and three quaternary carbons. This data accounted for all 1H and 13C resonances except for two exchangeable protons, and required 1 to possess a pentacyclic system. The 1H–1H COSY NMR data revealed the identification of four isolated proton spin-systems as the C-10-C-1-C-2-C-3, C-6-C-7-C-8, C-11-C-12, and C-14-C-15 fragments in the compound 1, and the remaining connectivity was determined by HMBC correlations (Fig. 2). The correlations from H2-1 to C-3, H-3 to C-4, C-5 and C-18, H2-19 to C-4, C-5, C-6, C-10 and C-8 connected the A and B rings, which established a 3a,4,5,6-tetrahydroisobenzofuran-1(3H)-one system. The HMBC correlations between CH3-20 and C-8, C-9, C-10 and C-11 fused the B and C rings. The key correlations from CH2-7 and H-12 to C-17 completed the connection of C and D rings. The distinct points in the HMBC spectrum of H-12 with C-13, C-14, C-16, and of H-14 with C-16, H-16 with C-15, and of two methoxy groups with C-15 and C-16, respectively, constructed a 2,5-dimethoxytetrahydrofuran ring system (E ring). Considering the molecular formula and chemical shift values of C-13 and C-14, there should have two carbons with hydroxyl groups in the compound 1. Thus the planar structure of 1 was determined. The relative configuration of 1 was established by NOESY correlations and analysis of coupling constant. The correlations from H-12 and H2-19 to CH3-20 put these protons on the same face of C and D ring, while the correlations between H-8 and H-10 suggested their opposite orientation on C ring; The correlation of H-15 and methoxyl-22 with H-14, and the small coupling constant between H-14 and H-15 (J=4.2Hz) implied that these two protons are on the same face of ring E. However, due to the single bond at C12-C13, the free rotation makes it impossible to establish the relative configuration of D ring and E ring. Thus, we determined the stereochemistry of 1 in two parts. Firstly, the stereochemistry of E ring was determined based on an existing diol at C-13 and C-14 by using Snaktzke’s CD method. The negative cotton effect at 290nm from inherent CD of 1 in DMSO subtracted from that of 1 in Mo2(OAc)4 solution indicated the absolute configuration of the diols as 13S,14S on the basis of applying of a heicity rule (Liu et al., 2010, Bari et al., 2001). Secondly, the absolute configuration of the others was determined from the Cotton effect of five-membered lactone ring. The CD spectrum of 1 showed the negative Cotton effect at 242nm, suggesting the absolute configuration of C-5 as 5S (Wagner et al., 1978). Thus, the stereochemistry of C-8, C-9, C-10, and C-12 was assigned as 8R, 9R, 10R, and 12S, respectively. Therefore, the stereochemistry of compound 1 was determined as 5S, 8R, 9R, 10R, 12S, 13S, 14S, 15R, 16R.