Design, synthesis and anticancer activity of novel 6-(aminophenyl)-2,4-bismorpholino-1,3,5-triazine derivatives bearing arylmethylene hydrazine moiety

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

“…As many PAC-1 derivatives show activity against white blood cell cancer lines ,,,,− and patient-derived leukemic lymphocytes in culture, the compounds were evaluated for their ability to induce cell death in a panel of lymphoma and leukemia cell lines, including Jurkat (human leukemia), GL-1 (dog lymphoma), OSW (dog lymphoma), and EL4 (mouse lymphoma) cells, to complement the previously determined IC 50 values in U-937 (human lymphoma) cells. As shown in Table , the compounds displayed comparable potency against each given cell line.…”

“…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.…”

“…Procaspase-activating compound 1 (PAC-1, 1 ; Figure ) was identified via a high-throughput screen for compounds that could enhance procaspase-3 enzymatic activity in vitro . PAC-1 is cytotoxic against a diverse array of cancer cells in culture, including cell lines derived from hematopoietic tumors (lymphoma, ,− leukemia, ,,− and multiple myeloma), carcinomas of diverse origin (breast, ,,− ,− renal, adrenal, , colon, ,,,,, lung, ,− ,− cervical, , gastric, ,,,,, ovarian, liver, ,, prostate, , and gallbladder , ), and other solid tumor histologies (melanoma, ,,, osteosarcoma, neuroblastoma, ,,, and glioblastoma , ). PAC-1 and its derivatives also induce apoptosis in patient-derived samples from colon cancer 8 and chronic lymphocytic leukemia, and have anticancer efficacy in multiple murine tumor models …”

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.…”

“…Because many PAC-1 derivatives induce cell death in white blood cell cancer lines [15, 24, 43, 44, 46, 48, 49, 52–55] and primary isolates from leukemia [23] and multiple myeloma patients [24] in culture, the cytotoxicity of the compounds in a series of lymphoma and leukemia cell lines, including Jurkat (human leukemia), GL-1 (dog lymphoma), OSW (dog lymphoma), and EL4 (mouse lymphoma) cells, in order to complement the previously determined IC 50 values in U-937 (human lymphoma) cells. As shown in Table 13, comparable potency was observed across each given cell line.…”