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The Mitogen-Activated Protein (MAP) kinases comprise a family of
serine/threonine kinases that function as critical mediators of signal transduction (Cohen, 1997; and
Ip and Davis, 1998). So far, four different MAP-kinases have been described:
the extracellular signal-related kinases (ERKs), the c-Jun N-terminal kinases (JNKs), the
p-38 MAP-kinases and the ERK5 or big MAP-kinase 1 (BMK1). The ERK
MAP-kinases play an important role in anti-estrogen growth inhibition in breast cancer (Kyriakis
and Avruch, 2001). Mitogens activate the ERK MAP-kinase protein. The JNK and
p-38 MAP-kinases are reactive to stress and inflammatory cytokines.
Hexamethyl Melamine (HMM), a derivative of triazine-A (Figure 1), possesses
various pharmacological actions against breast, lungs and ovarian cancers, but causes
nausea, vomiting, abdominal cramps and anorexia. Compound B (Figure 1) was investigated
by Moon et al. (2002) as a microbial destabilizing agent entity with potent growth
inhibition against U937 cells (GI50 =1 mm). Leftheris et al. (2004) reported compounds C and
D (Figure 1) as potent inhibitors of p-38 MAP-kinase.
Compound E (triaminotriazine derivatives) (Figure 2) was recently reported by Baindur et al. (2005) as a potent VEGF-R2 (KDR) tyrosine kinase inhibitor. Therefore it is
a common feature for triazine derivatives to exhibit antitumor
activities. Zheng et al.
(2007) introduced various aryl amino groups into the triazine scaffold and calculated
their biological activity. Taking the experimental activity from the work of Zheng et al. as the dependent variable, we formulate
a mathematical model based on graph theoretical indices, quantum chemical and
structural parameters to design a number of potent triazine scaffold-based
inhibitors. |
