Abstract
The incentive of the present work has been primarily directed towards the design and synthesis of some novel pyrido[1,2-a]benzimidazoles with specific functionalities believed to have alkylation ability. This combination of pharmacological agents may enable synergistic anticancer effect. Nine compounds 5b, 13a, 13d, 13e, 14b, 14c, 15, 16, and 17 were selected by the National Cancer Institute (NCI), Bethseda, Maryland, USA to be evaluated for their in vitro antitumor activity. All the selected compounds were tested initially at a single dose (10 μM) in the full NCI 60 cell panel including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancer cell lines. Majority of the test compounds exhibited moderate cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by 14c against melanoma SK-MEL-5 cell line. This may be due to the impact of the lipophilic trifluoromethyl substitution on the biological activity profile.
Highlights
IntroductionCancer is a devastating affliction, the frequency of which is progressively increasing all over the world
The treatment approach dictates that the treatment of cancer is directed toward eradication of all cancer cells and this is attained by frenziedly discovery of new candidates of anticancer activity [2]
The 2-pyridone unit is an integral part of some cytotoxic agents such as roquinimex which investigated as adjuvant therapy after bone marrow transplantation in chronic myelogenous leukemia [17] and diazaquinomycin A which demonstrates in vitro cytotoxicity against some tumor cell lines [18]
Summary
Cancer is a devastating affliction, the frequency of which is progressively increasing all over the world. We have utilized pyrido[1,2-a]benzimidazole (PBI) as a privileged scaffold for the design of many PBI derivatives of potential cytotoxic activity [3-8] This ring system is characterized by the presence of pyridine or 2-pyridone units which constitute a subject of great interest due to their extensive presence in the skeletal backbone of many biologically active compounds. It is proposed that the planar nature of camptothecin allows its intercalation between DNA base pairs at the site of single-strand cleavage [21] For this reason, it may be worthy to study the possible interactions of NSC649900, NSC682011 and NSC699944 with topisomerase-I as a target enzyme because of the evident structural complementarity between PBI scaffold of these agents and pyrido[2,3-a]indolizine (PI) backbone of camptothecin (Figure 2).
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