Two new premyrsinane-type diterpenes
(2 and 3) as diastereomers were synthesized
from lathyrane-type diterpene
euphorbia factor L3 (1) for the first time
via an efficient Fe(acac)3-catalyzed skeleton conversion
process. This conversion features a biogenetically inspired strategy
that relies on a concise reductive olefin coupling involving intramolecular
Michael addition with free radicals. The structures of 2 and 3 were elucidated by a combination of the interpretation
of their spectroscopic data and single-crystal X-ray diffraction analysis.
The premyrsinane diterpenes 2 and 3 exhibited
cytotoxic activity against the 4T1 breast cancer cell line, while
the parent compound euphorbia factor L3 (1) was inactive. The current results not only confirmed the biogenetic
relationship between lathyranes and premyrsinanes for the first time
but also suggested a novel method for the preparation of naturally
rare premyrsinane diterpenes with high bioactivity from the more abundant
natural lathyrane diterpenes.
The biorelevant sulfur-containing Euphorbia diterpenes with scarce 5/7/6/3 premyrsinane-and 5/7/6 myrsinanetype backbones were easily constructed from naturally abundant lathyrane-type Euphorbia factor L 3 by visible-light-triggered tandem thiol−ene click reaction/transannular cyclization and regioselective cyclopropane ring-opening. The selenide diterpene was also successfully obtained to verify the system universality. This concise synthesis route gives an efficient strategy for obtaining structurally diverse Euphorbia diterpenes under very mild conditions and provides a promising anti-HIV bioactive premyrsinane diterpene 3h.
Five new aconitine-type C 19 -diterpenoid alkaloids, apetalrines A−E (1−5), were isolated from Aconitum apetalum. Their structures were determined by analysis of 1D and 2D NMR, IR, and HRESIMS data. Semisynthesis of apetalrine B (2) from its parent compound aconorine was achieved to confirm the structure proposed. Twenty derivatives of 2 (11a−11l, 12a, 12b, 12d, 12e, 12j, 12k, 12m, 12n) were synthesized via a unified approach relying on simple coupling reactions. The evaluation of neuroprotective effects of compounds (1−5, 11b, 11c, 11f−11i, 12a, 12b, 12d, 12e, 12k, 12m, 12n) with low cytotoxicity revealed compound 2 to exhibit good neuroprotective effects in H 2 O 2 -treated SH-SY5Y cells at a concentration of 50 μM. A series of studies using flow cytometry, staining, and Western blotting on 2 indicated that its neuroprotective effects may arise from inhibiting cell apoptosis.
The first systematic direct diversification
of a complex natural
product by metal-catalyzed N–H functionalization was carried
out. A new series of N-(hetero)aryl analogues (1–32) of the natural anti-Alzheimer’s
disease drug huperzine A (HPA) was prepared via palladium-catalyzed
Buchwald–Hartwig cross-coupling reactions of HPA with various
aryl bromides in good yields. Most of the N-aryl-huperzine
A (N-aryl-HPA) analogues showed good acetylcholinesterase
(AChE) inhibitory activity in in vitro experiments.
Three arylated huperzine A analogues (14, 19, and 30) exhibited stronger anti-AChE activity than
HPA. The 5-methoxy-2-pyridyl analogue (30) displayed
the most potent AChE inhibition activity, with an IC50 value
of 1.5 μM, which was 7.6-fold more active than HPA. Compound 30 also exhibited better neuroprotective activity for H2O2-induced damage in SH-SY5Y cells than HPA. Structure–activity
relationship analysis suggested that the electron density of the installed
aromatic ring or heteroaromatic ring played a significant role in
inducing the AChE inhibition activity. Overall, compound 30 showed the advantages of easy synthesis, high potency and selectivity,
and improved neuroprotection, making it a potential huperzine-type
lead compound for Alzheimer’s disease drug development.
A new series of
N
-aryltacrine derivatives were
designed and synthesized as cholinesterase inhibitors by the late-stage
modification of tacrine, using the palladium-catalyzed Buchwald–Hartwig
cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase
(AChE) and butyrylcholinesterase (BuChE) demonstrated that most of
the synthesized compounds had potent AChE inhibitory activity with
negative inhibition of BuChE. Among them,
N
-(4-(trifluoromethyl)phenyl)-tacrine
(
3g
) and
N
-(4-methoxypyridin-2-yl)-tacrine
(
3o
) showed the most potent activity against AChE (IC
50
values of 1.77 and 1.48 μM, respectively). The anti-AChE
activity of
3g
and
3o
was 3.5 times more
than that of tacrine (IC
50
value of 5.16 μM). Compound
3o
also displayed anti-BuChE activity with an IC
50
value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y
cell lines revealed that
3o
had significantly lower hepatotoxicity
compared to tacrine, with additional neuroprotective activity against
H
2
O
2
-induced damage in SH-SY5Y cells. The advantages
including synthetic accessibility, high potency, low toxicity, and
adjunctive neuroprotective activity make compound
3o
a
new promising multifunctional candidate for the treatment of Alzheimer’s
disease.
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