Daphneodorins A–C, Anti-HIV Gnidimacrin Related Macrocyclic Daphnane Orthoesters from Daphne odora

Abstract

Three novel gnidimacrin related macrocyclic daphnanes (GMDs), daphneodorins A-C (2-4), were isolated from Daphne odora Thunb., together with gnidimacrin (1). Their structures were established by extensive physicochemical and spectroscopic analyses. Compounds 2 and 3 potently inhibited HIV-1 replication at subnanomolar concentrations (EC 50 0.16 and 0.25 nM, respectively). Compounds 2-4 represent a novel type of GMDs that are highly oxygenated on the macrocyclic ring, suggesting good potential for anti-HIV drug development by further chemical modification.

Identification of anti-HIV macrocyclic daphnane orthoesters from Wikstroemia ligustrina by LC–MS analysis and phytochemical investigation

“…In the macrocyclic ring part, the NOESY correlation between H 3 -10′/H-2 and H 3 -10′/H-10 suggested that CH 3 -10' has the β-orientation. The chemical shift of CH 3 -10′ in 1 (δ C 13.0) was also in good agreement with the previously reported value when it was β-orientation[3][4][5]16], whereas the CH 3 -10' epimer of 1, genkwadane B, was reported at δ C 19.0[17].Four peaks (3, 4, 6, and 7) detected in the LC-MS analysis could not be isolated, and their structures were deduced by the information of molecular formula, retention time, and MS/MS fragmentation pattern. Peak 6 was identified as gnidimacrin by comparison with the standard compound.…”

“…Although weaker than the positive control, gnidimacrin (6), they still showed potent anti-HIV activity, of which compounds 1, 2 and 8 with IC 50 < 1 nM. The MDOs 2 (IC 50 0.44 nM) and 6 (IC 50 0.08 nM) exhibited more potent activity than 1 (IC 50 0.99 nM) and 5 (IC 50 3.61 nM), suggesting that the benzoyl group at C-3 is favorable for anti-HIV activity than at C-20 [5,12]. As for nonmacrocyclic daphnanes (8, IC 50 0.69 nM versus 9, IC 50 5.86 nM), a saturated aliphatic chain which attached at C-1′ was favorable for anti-HIV activity than the unsaturated aliphatic chain.…”

“…Macrocyclic daphnane orthoester (MDO) attributes the characteristic of the structure that 1-alkyl at daphnane skeleton forms a macrocyclic ring through an orthoester moiety [1]. This type of daphnanes have shown extremely potent dual action to inhibit HIV-1 replication and active latent HIV-1, which have attracted significant research interest for the drug discovery to cure HIV infection based on the "Shock and Kill" strategy [2][3][4][5]. However, as far as our best understanding of MDO is concerned, the occurrence of such compounds in the plant kingdom is still quite limited, which greatly hindered the development of MDOs as new anti-HIV drugs.…”

“…However, as far as our best understanding of MDO is concerned, the occurrence of such compounds in the plant kingdom is still quite limited, which greatly hindered the development of MDOs as new anti-HIV drugs. Previous phytochemical investigations have resulted in the isolation of MDOs from some genera of Thymelaeaceae family, including Daphne, Gnidia, Pimelea, Stellera, and Wikstroemia [1][2][3][4][5][6][7][8]. As hinted by that MDO compounds have been reported from W. retusa [6] and W. chamaedaphne [7,8], we set up a plant collection of Wikstroemia species, which included W. ligustrina.…”

Discovering the Mechanisms of Wikstroelide E as a Potential HIV-Latency-Reversing Agent by Transcriptome Profiling

“…6,7 In particular, gnidimacrin potently inhibited HIV-1 replication in assays of HIV replication, which was 5000-and 500-fold greater than the inhibition induced by prostratin and the HIV-1 antiretroviral drug zidovudine (AZT), respectively. 8 Such results encourage the investigation of various tigliane and daphnane diterpenes as novel anti-HIV agents for research and clinical studies.…”