Structurally diverse hamigerans from the New Zealand marine sponge Hamigera tarangaensis: NMR-directed isolation, structure elucidation and antifungal activity

Abstract

The NMR-directed investigation of the New Zealand marine sponge Hamigera tarangaensis has afforded ten new compounds of the hamigeran family, and a new 13-epi-verrucosane congener. Notably, hamigeran F (6) possesses an unusual carbon–carbon bond between C-12 and C-13, creating an unprecedented skeleton within this class. In particular, the structural features of 6, hamigeran H (10) and hamigeran J (12) imply a diterpenoid origin, which has allowed the putative biogenesis of three hamigeran carbon skeletons to be proposed based on geranyl geranyl pyrophosphate. All new hamigerans exhibited micromolar activity towards the HL-60 promyelocytic leukaemic cell line, and hamigeran G also selectively displayed antifungal activity in the budding yeast Saccharomyces cerevisiae. Homozygous deletion profiling (HOP) analysis suggests Golgi apparatus function as a potential target of this unusual class of sponge-derived terpenoids.

Antifungal and antiviral products of marine organisms

“…Homozygous deletion profiling analysis disclosed Golgi apparatus as its potential target (Singh et al 2013). …”

Hamigeran G Does Not Affect Golgi Structure or Function in HEK293 Cells

“…In a preliminary study, hamigeran G was tested on wildtype HL-60 and mitochondrial gene knockout HL-60 cells (HL-60 0 ). We found that there was only a twofold increase in IC50 for HL-60 0 compared to that of the wildtype HL-60 [5]. This increase in resistance to hamigeran G is relatively small and indicates that the mitochondrion is unlikely to be the primary target of hamigeran G and therefore, other target(s) of hamigeran G must exist in the cell.…”

“…The hamigerans are structurally related diterpenoid secondary metabolites that were first isolated from the New Zealand marine sponge, Hamigera tarangaensis (Bergquist and Fromont, 1988). Currently, 34 naturally occurring hamigerans have been reported [3][4][5][6][7]. These compounds show a range of biological activity that includes anticancer, antibacterial, antifungal, and antiviral activity.…”

“…Researchers at Victoria University of Wellington were responsible for isolating 26 of the 34 different hamigerans, and of these 26, hamigeran G showed the most potential as an anticancer drug and therefore, was chosen for further research. The hamigerans were tested for anti-proliferative activity against the HL-60 human promyelocytic leukemia cell line, and hamigeran G was found to be the most cytotoxic, with an IC50 in the low micromolar range [5]. Initial studies in our laboratory on cell cycle effects demonstrated only slight accumulation of cells in G2/M of the cell cycle, making it unlikely that hamigeran G was targeting the cytoskeleton as an antimitotic agent.…”

“…To identify a possible mechanism of action or target(s) of hamigeran G's anti-proliferative activity, a chemical genetic screen involving haploinsufficiency profiling was carried out on Saccharomyces cerevisiae [5,8]. The screen identified three mitochondrial genes (CYC1, HMF1, and FLC3) as possible targets.…”