Abstract
Experimental Approach: Colorectal cancer (CRC) is the third leading
cause of cancer-related deaths in men and in women. It’s expected to
cause about 53,200 deaths during 2020. An effective drug for therapy and
prognosis after surgery still does not exist. Therefore, the search for
new lead structures and chemical entities for the development of new
effective anticancer agents is an increasingly important task in
medicinal chemistry. This trend of global research includes work on the
use of 1,2,4-triazine scaffold as a source for the design of
biologically relevant molecules with well-known broad biological
applications. A series of new
pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamides
were designed, synthesized, and assessed as anticancer activity agents.
Experimental Approach: The impact of two selected compounds, MM-128, and
MM-129 (MMs), were evaluated against human colon cancer in in vitro and
in zebrafish embryo xenograft model. Key Results: Our results show that
the new synthesized compounds effectively inhibit cell survival and DNA
synthesis in both DLD-1 and HT-29 cell lines. Their effectiveness is
much higher as compared with the standard chemotherapy used for
colorectal cancer, i.e. 5-fluorouracil. Flow cytometry analysis after
annexin V-FITC and propidium iodide staining revealed that apoptosis was
the main response of colorectal cancer cells to MMs treatment. We also
found that MM-129 effectively inhibits tumor development in both DLD-1
and HT-29 zebrafish xenografts. Conclusion and Implications: New
pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamides
may be new candidates for further evaluation as chemotherapeutic agents
against colorectal cancer.