Medicinal Chemistry of Probimane and MST-16: Comparison of Anticancer Effects Between Bisdioxopiperazines

Abstract

Bisdioxopiperazines, including ICRF-154 and razoxane (ICRF-159, Raz), are a family of anticancer agents developed in the UK, specifically targeting neoplastic metastases. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. In order to determine the similarities and differences between these agents in medical chemistry, we evaluated the anti-tumor and anti-metastatic effects of Pro and MST-16 in vitro and in vivo against a number of human tumor cell lines and one of murine origin (Lewis lung carcinoma, LLC), and one human tumor xenograft (LAX-83) in nude mice. Our results show that Pro was cytotoxic to human tumor cell lines in vitro (IC50 < 50 microM for 48 h), approximately 3 to 20-fold more than MST-16. Pro and MST-16 manifested more prolonged cytotoxicity than some other first-line anticancer drugs including 5-fluorouacil, vincristine and doxorubicin, and maintain their cytotoxic effects for 4 days in vitro. In animal experiments, Pro and Raz were active against primary tumor growth (35-50 %) and significantly inhibited pulmonary metastasis of LLC (inhibition > 90 %) at dosage below LD(5). Both Raz and Pro were effective in administration schedules of 1, 5 and 9 days. Both Raz (25-32 %) and Pro (55-60 %) caused statistically significant inhibition of the growth of LAX 83 (a human lung adeno-carcinoma xenograft) in nude mice. In this model, Pro was more effective against LAX83 than Raz at equitoxic dosages. These findings suggest that Pro is active against more categories of tumors both in vivo and in vitro, which in some circumstances may make it superior to the currently-used anticancer bisdioxopiperazines, including razoxane and MST-16.

Different Spontaneous Pulmonary Metastasis Inhibitions against Lewis Lung Carcinoma in Mice by Bisdioxopiperazine Compounds of Different Treatment Schedules

“…From our early data of 14 C-probimane tracing and autoradiography [24, 25], an obvious greater accumulation of Pro was found in tumor tissues, especially in metastatic foci. It can help to explain that Pro can more effectively inhibition of neoplasm metastasis than Raz in formed metastatic foci through stronger antiproliferative effect [13, 14]. Their molecular mechanisms of action may be attributed to their inhibition of CaM-activated Ca ++ -Mg ++ -ATPase [26].…”

“…Biological inoculation with pulmonary nodules of 3LL was a method used by Yue et al [14]. C57BL/6j mice were implanted sc with LLC (2×10 6 cells) from donor mice.…”

Absorption, Distribution and Excretion of 14C-Probimane in Mice Bearing Lewis Lung Carcinoma

“…The inhibition of neoplasm metastasis by Raz has been previously explained as a result of reduction in the formation of blood vessels in primary tumor tissues (neovasculature) [10–12]. Thus, it has been proposed that Raz remains ineffective against the pulmonary metastases of 3LL (formed metastatic foci) [15] and nevertheless Pro can be more effective in the inhibition of neoplasm metastasis than Raz in formed metastatic foci through stronger antiproliferative effect [8, 9] and drug accumulation. From this data of 14 C-Pro tracing, an obvious greater accumulation of Pro was found in tumor tissues, especially in metastatic foci.…”

“…Bisdioxopiperazine compounds (Biz), including ICRF-154, Razoxane (ICRF-159, Raz ), ICRF-186 and ICRF-187 (two stereo-isomers of Raz) and ICRF-193, developed in the UK, have been a series of serendipitous agents found to be effective against a model of spontaneous metastasis (Lewis lung carcinoma, 3LL) [4, 5]. Since Biz compounds are unique and conservative in pharmacological actions, their new analog Probimane [4,4′-(propane-1,2-diyl)bis[1-(morpholin-4-ylmethyl)piperazine-2,6-dione; AT-2153, Pro] [6–9] was synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Since previous data showed that Pro has good antiproliferative effects in vitro [8] and moderate anticancer activity against the growth Lewis lung carcinoma in vivo [7], further work to specialized determinations of these characters is imperative and helpful to us.…”