Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

Abstract

Novel silyl cyanocinnamic acid derivatives have been synthesized and evaluated as potential anticancer agents. In vitro studies reveal that lead derivatives 2a and 2b have enhanced cancer cell proliferation inhibition properties when compared to the parent monocarboxylate transporter (MCT) inhibitor cyano-hydroxycinnamic acid (CHC). Further, candidate compounds exhibit several-fold more potent MCT1 inhibition properties as determined by lactate-uptake studies, and these studies are supported by MCT homology modeling and computational inhibitor-docking studies. In vitro effects on glycolysis and mitochondrial metabolism also illustrate that the lead derivatives 2a and 2b lead to significant effects on both metabolic pathways. In vivo systemic toxicity and efficacy studies in colorectal cancer cell WiDr tumor xenograft demonstrate that candidate compounds are well tolerated and exhibit good single agent anticancer efficacy properties.

Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1)

“…We obtained compounds with higher inhibitory potency compared to a significant fraction of the ∼100 reported MCT1 inhibitors in the literature, 18−31 including pteridine derivatives, 33 most coumarin derivatives, 25 and many cinnamic acid derivatives including reference compound 8. 21,24,31 Nevertheless, many earlier reported MCT1 inhibitors have demonstrated inhibition concentrations significantly below the determined IC 50 values as found within our work, 18 including thieno[2,3-d]pyrimidin-2,4-diones, 28,32 pyrrolo [3,4-d]pyridazinones, 29 or 7 34 as well as many cinnamic acid derivatives. 22,24 However, three aspects have to be considered to put the bioactivity profile of indole derivatives into the right perspective:…”

“…These diverse assays included nonfunctional MTT-based cell viability assays, 21,25,33 pH-dependent functional fluorescence assays, 34 functional radiotracer assays [e.g., 3 H-labeling of test candidates, 34 14 C-labeling of MCT1 substrates ( 14 C-lactate 21,22,24,25,31,33,34 ), or photoaffinity labeling (e.g., by 125 I-labeling 29 )]�often focusing on binding a ffi n i t y 2 9 , 3 4 r a t h e r t h a n i n h i b i t o r y p o w e r (IC 50 ). 21,22,24,25,31,33,34 Furthermore, the applied cell lines were diverse, including either genuine MCT1-(over)expressing (cancer) cells (e.g., A-549, 14,15 DLD-1, 34 MCF-7, 16,21,33 RBE4, 21,22,24 or SiHa 25 ) but also transfected artificial expression systems (e.g., Xenopus laevis oocytes 31,34 )�both of which showed differences in MCT1 expression, resulting in variations in assay response and bioactivity data. Thus, the data presented in our work can only to a very limited extent be compared to literature data, as literature data itself can only be compared with each other to a limited extent in the current data situation.…”

“…, compound 5 ), coumarin derivatives ,, [ e.g. , 7ACC2 ( 6 )], the sulfonyldibenzene BAY‑8002 ( 7 ), ,, as well as cinnamic acid derivatives ,,,, [ e.g. , hydroxy-4-cyanocinnamic acid (CHC); 8 ]. , Figure shows the molecular structures of compounds 1 – 8 .…”

“…18−31 Certain drugs and druglike compounds have been reported to inhibit MCT1, 26,30,31 such as benzbromarone (1) 31 and quercetin (2), 31 however, with rather low potency. Amongst the high-throughput screening-(HTS)-and organic synthesis-derived compounds, only a few structurally distinctive compound classes can be differentiated: (i) thieno [2,3d]pyrimidin-2,4-diones, 18,27−29 [e.g., AZD-3965 (3) 32 ], pteridine derivatives 18,19,33 (e.g., compound 4 33 ), pyrrolo [3,4d]pyridazinones 18,23,29 (e.g., compound 5 29 ), coumarin derivatives 18,19,25 [e.g., 7ACC2 (6) 25 ], the sulfonyldibenzene BAY-8002 (7), 18,19,34 as well as cinnamic acid derivatives 18,21,22,24,31 [e.g., hydroxy-4-cyanocinnamic acid (CHC); 8]. 18,31 Figure 1 shows the molecular structures of compounds 1−8.…”

Synthesis, in vitro, and in vivo evaluation of novel N-phenylindazolyl diarylureas as potential anti-cancer agents

“…Cellular viability in the presence of test compounds in 4T1, GL261-luc2, MDA-MB-231, MIAPaCa-2, and WiDr cancer cells was determined using MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay as previously described by us 36 . Dose response curves in Fig.…”