Synthesis and Biological Evaluation of Benzothiazole Derivatives Bearing the ortho‐Hydroxy‐N‐acylhydrazone Moiety as Potent Antitumor Agents

Abstract

A novel series of benzothiazole derivatives bearing the ortho-hydroxy-N-acylhydrazone moiety were designed, synthesized, and evaluated for their procaspase-3 kinase activation activities and antiproliferative activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN-45, and MDA-MB-231). Most target compounds showed moderate to excellent cytotoxic activity against all five tested cancer lines. The most promising compound 18e (procaspase-3 EC50 = 0.31 µM) with IC50 values ranging from 0.24 to 0.92µM against all tested cell lines was 4.24-12.2 times more active than PAC-1 (procaspase-3 EC50 = 0.41 µM). Structure-activity relationship studies indicated that the phenyl group on the 2-hydroxyphenyl ring (moiety A) was critical for pharmacological activity in vitro. In addition, introduction of a benzyloxyl group on moiety A and a mono-electron-withdrawing group at the 4-position of the benzyloxyl group were more favorable for antitumor activity. Moreover, reduction of the electron density in the phenyl ring of the benzyloxy group led to a dramatic decrease in the procaspase-3 kinase activation activity.

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

“…8 PAC-1 has been shown to be cytotoxic against a diverse array of cancer cells in culture, including cell lines derived from hematopoietic tumors (lymphoma, 8, 36–43 leukemia, 8, 38, 42–47 and multiple myeloma 47 ), carcinomas of diverse origin (breast, 8, 38, 42–46, 48–50 renal, 8 adrenal, 8, 51 colon, 8, 42, 47, 49, 50, 52 lung, 8, 42–50, 52–55 cervical, 38, 47 gastric, 42, 43, 47, 49, 50, 52 ovarian, 47 liver, 42, 43, 47 prostate, 42, 43 and gallbladder 42, 43 ), and other solid tumor histologies (melanoma, 8, 38, 42, 43 osteosarcoma, 47 neuroblastoma, 8, 47, 49, 50 and glioblastoma 42, 43 ). PAC-1 and derivatives also induce apoptosis in patient-derived samples from colon cancer 8 and chronic lymphocytic leukemia, 18 and have anticancer efficacy in multiple murine tumor models 8, 42, 43, 48, 54–56 and in pet dogs with cancer.…”

Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

“…[15] PAC-1 and its derivatives induce apoptosis and are cytotoxic in cell culture to a diverse array of cancer cells, including cell lines derived from white blood cell cancers (lymphoma, [15, 42–51] leukemia, [15, 24, 44, 48–50, 52–55] and multiple myeloma [24, 55]), diverse carcinomas (breast, [15, 44, 48, 49, 52–54, 56–59] renal, [15] adrenal, [15, 60–62] colon, [15, 48, 55, 57–59, 63] lung, [15, 48, 49, 52–59, 63–67] cervical, [44, 55] gastric, [48, 49, 55, 57, 58, 63] ovarian, [55] liver, [48, 49, 55] prostate, [48, 49] and gallbladder [48, 49]), and other solid tumor types (melanoma, [15, 44, 48, 49] osteosarcoma, [55] neuroblastoma, [15, 55, 57, 58] and glioblastoma [48, 49, 68]). Patient-derived samples from colon cancer [15], chronic lymphocytic leukemia [23], and multiple myeloma [24] are also sensitive to PAC-1 and derivatives, and a therapeutic effect has been demonstrated in multiple murine tumor models [15, 48, 49, 56, 65, 66, 69] and in pet dogs with cancer.…”

“…[57, 58] The benzothiazole derivatives were substituted at the 6-position to block metabolism. Positively-charged substituents were chosen in order to mimic the piperazine nitrogen atoms present in PAC-1 .…”

“…Positively-charged substituents were chosen in order to mimic the piperazine nitrogen atoms present in PAC-1 . [57, 58] The first series (Table 5) contained 26 derivatives ( 26a–z ). [57] Cytotoxicity of the compounds was evaluated over 72 hours in HT-29 (human colon cancer), MDA-MB-231 (human breast cancer), MKN-45 (human gastric cancer), NCI-H226 (human lung cancer), and SK-N-SH (human neuroblastoma) cell lines in culture.…”

“…Importantly, the semicarbazone proved to be an acceptable replacement for the hydrazone of PAC-1 , as compounds retained potency in the cell lines tested. [57]…”