Abstract
Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM–100 µM) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.
Highlights
Pancreatic cancer (PC) remains a devastating disease; it is the fourth most common cause of cancer death in the Western world [1] and is projected to be the second leading cause of cancer death by2030 [2]
A major challenge of PC is that it is highly resistant to current chemotherapy drugs [4] and without effective chemotherapy options available for PC patients, a pressing need exists for the continued discovery of novel drug candidates
The desired symmetrical bispidinones were prepared from readily accessible starting materials
Summary
Pancreatic cancer (PC) remains a devastating disease; it is the fourth most common cause of cancer death in the Western world [1] and is projected to be the second leading cause of cancer death by2030 [2]. A major challenge of PC is that it is highly resistant to current chemotherapy drugs [4] and without effective chemotherapy options available for PC patients, a pressing need exists for the continued discovery of novel drug candidates. Drug development from synthetic compounds and synthetic analogues of pharmacophores in natural products provides the benefit of structural modification of drug candidates to improve potency, selectivity, and bioavailability [5,6]. Plant alkaloids in particular are traditional starting points for drug development, with many compounds in this class possessing potent biological activity. The bispidine ring system (3,7-diazabicyclo[3.3.1]nonane) is an unusual heterocyclic compound consisting of two piperidine rings fused at a common three carbon junction and is the base structure for the quinolizidine plant alkaloids, including sparteine and related analogues cytisine and anagyrine. Sparteine exhibits antiarrhythmic and antibacterial properties, while cytisine and associated derivatives display analgesic, antihypertensive, antispasmodic, and antidepressant activities [7,8,9,10,11]
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