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PC-50

Selective cytotoxic diterpenoids featuring a 4/9-fused ring system from the

soft coral Sclerophytum humesi

3
2
3
Phuong Vu Luu, Thuy-Tien Thi Phan, Ngoc-Thac Pham, Huong-Giang Le, Lo-Yun
#,1
Chen, Bo-Rong Peng,* ,1,3,4 Kuei-Hung Lai* ,1,3,5
3

1 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University,
Taipei 110301, Taiwan
2 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical
Engineering, Taipei Medical University, Taipei, 11031, Taiwan
3 PhD Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy,
Taipei Medical University, Taipei 110301, Taiwan
4 Graduate Institute of Healthy Industry Technology, Center for Drug Research and
Development, College of Human Ecology, Chang Gung University of Science and
Technology, Taoyuan 333324, Taiwan
5 Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei
110301, Taiwan
* E-mail: kueihunglai@tmu.edu.tw

Abstract
Twenty new terpenoids, including fourteen diterpenoids (1-14), five norsesquiterpenoids (15-
19), one dimeric diterpenoid (20), and ten known compounds (21-30), were isolated from the
soft coral Sclerophytum humesi by bioassay-guided isolation. These compounds feature a 4/9-
fused ring system, which was first isolated from the genus Sclerophytum. Among them,
compounds 1, 2, and 15 represent new carbon skeletons with 4/7/12-, 4/8/5-, and 5/7/6-fused
systems, respectively. Furthermore, compound 20 represents a rare dimer, the first example of
a metabolite formed from two xeniaphyllane diterpenoids through a unique 16-peroxyl bridge.
Their structures were elucidated through comprehensive spectroscopic analyses, including
NMR, HRESIMS, ECD, and DP4+ probability assessments. All isolates were evaluated for
cytotoxic and antidiabetic activities. Compounds 1-9 exhibited selective cytotoxicity against
the MIA PaCa-2 cell line, with IC50 values ranging from 1.35 to 26.13 µM and SI > 3. Western
blot analysis further revealed that compound 3 induces intrinsic apoptosis in pancreatic cancer
cells via caspase-dependent cleavage of PARP1. In addition, diterpenoids (1-14) demonstrated
significant multitarget inhibitory activity against enzymes α-amylase, α-glucosidase, and lipase,
with IC50 values ranging from 16.1 to 170.0 µM. Enzyme kinetics, molecular docking, and
molecular dynamics simulations were also performed to further elucidate the experimental
findings. These results highlight the potential of marine-derived terpenoids as promising
multifunctional bioactive agents with therapeutic applications in the management of diabetes
and pancreatic cancer.

Keywords: Sclerophytum humesi; Pancreatic cancer; PARP1; Molecular docking; Molecular
dynamics