Novel tumor-targeting dual-warhead
conjugates, 2 (DW-1)
and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative
disulfide linkers for drug release, biotin as the tumor-targeting
moiety, and 1,3,5-triazine as the tripod splitter module, were designed
and synthesized. The potency of 2 was evaluated against
MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and
WI38 (BR–, normal) cell lines in the absence and presence of
glutathione (GSH), which is an endogenous thiol that triggers drug
release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22–9.80 nM
against all BR+ cancer cell lines, and 705 nM against WI38. Thus,
there was a two orders of magnitude higher selectivity to cancer cells.
Also, a clear cooperative effect was observed for the taxoid–camptothecin
combination when two drugs were delivered to the cancer cells specifically
in the form of a dual-warhead conjugate.
A lack
of target specificity has greatly hindered the success of
inhibitor development against matrix metalloproteinases (MMPs) for
the treatment of various cancers. The MMP catalytic domains are highly
conserved, whereas the hemopexin-like domains of MMPs are unique to
each family member. The hemopexin-like domain of MMP-9 enhances cancer
cell migration through self-interaction and heterointeractions with
cell surface proteins including CD44 and α4β1 integrin.
These interactions activate EGFR-MAP kinase dependent signaling that
leads to cell migration. In this work, we generated a library of compounds,
based on hit molecule N-[4-(difluoromethoxy)phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl)sulfanyl]-acetamide, that target the hemopexin-like
domain of MMP-9. We identify N-(4-fluorophenyl)-4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-ylthio)butanamide, 3c, as a potent lead (Kd = 320
nM) that is specific for binding to the proMMP-9 hemopexin-like domain.
We demonstrate that 3c disruption of MMP-9 homodimerization
prevents association of proMMP-9 with both α4β1 integrin
and CD44 and results in the dissociation of EGFR. This disruption
results in decreased phosphorylation of Src and its downstream target
proteins focal adhesion kinase (FAK) and paxillin (PAX), which are
implicated in promoting tumor cell growth, migration, and invasion.
Using a chicken chorioallantoic membrane in vivo assay,
we demonstrate that 500 nM 3c blocks cancer cell invasion
of the basement membrane and reduces angiogenesis. In conclusion,
we present a mechanism of action for 3c whereby targeting
the hemopexin domain results in decreased cancer cell migration through
simultaneous disruption of α4β1 integrin and EGFR signaling
pathways, thereby preventing signaling bypass. Targeting through the
hemopexin-like domain is a powerful approach to antimetastatic drug
development.
Naturally occurring hyacinthacines B1 and B2 have been prepared from a common, easily available, advanced intermediate. The approach features several highly stereoselective transformations: inter alia, a dichloroketene-enol ether [2 + 2] cycloaddition, a Bruylants alkylation, and an amino-nitrile alkylation-reduction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.