Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase.

Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho-substituted compounds were more active than meta- or ortho-substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids.

Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7-46.9 µM and 26.8-43.1 µM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.

Design, synthesis and evaluation of alkylphosphocholine-gefitinib conjugates as multitarget anticancer agents.

The evolving resistance to the currently used chemotherapeutic agents requires continuous efforts to develop new anticancer agents overcoming resistance and with lower side effects. Polypharmacology via designing a single molecule intercepting multiple signaling pathways is more effective than targeting a single one. Several alkylphosphocholines show anticancer activity via inhibition of Akt phosphorylation. On the other hand, several molecules having quinazoline scaffold elicit anticancer activity through inhibition of epidermal growth factor receptor (EGFR) tyrosine kinases. We report our efforts to develop alkylphosphocholines-gefitinib conjugates as multitarget anticancer agents. The antiproliferative activities of the newly synthesized compounds were evaluated against cell lines representing lung, breast, liver and skin cancers. In addition, the capability of the newly synthesized compounds to inhibit Akt phosphorylation and EGFR tyrosine kinases were determined. The results emphasized the influence of the linkers' length on the elicited bioactivity. The long chain linkers possessing conjugates were more active regarding both of the elicited antiproliferative effect and inhibition of Akt phosphorylation, while maintained the ability to inhibit EGFR tyrosine kinases. Their cytotoxic activities were superior or comparable to erlotinib and miltefosine.

Novel C6-substituted 1,3,4-oxadiazinones as potential anti-cancer agents.

The insulin-like growth factor 1 receptor (IGF-1R) is a membrane receptor tyrosine kinase over-expressed in a number of tumors. However, combating resistance is one of the main challenges in the currently available IGF-1R inhibitor-based cancer therapies. Increased Src activation has been reported to confer resistance to anti-IGF-1R therapeutics in various tumor cells. An urgent unmet need for IGF-1R inhibitors is to suppress Src rephosphorylation induced by current anti-IGF-1R regimens. In efforts to develop effective anticancer agents targeting the IGF-1R signaling pathway, we explored 2-aryl-1,3,4-oxadiazin-5-ones as a novel scaffold that is structurally unrelated to current tyrosine kinase inhibitors (TKIs). The compound, LL-2003, exhibited promising antitumor effects in vitro and in vivo; it effectively suppressed IGF-1R and Src and induced apoptosis in various non-small cell lung cancer cells. Further optimizations for enhanced potency in cellular assays need to be followed, but our strategy to identify novel IGF-1R/Src inhibitors may open a new avenue to develop more efficient anticancer agents.

Synthesis, characterization and Akt phosphorylation inhibitory activity of cyclopentanecarboxylate-substituted alkylphosphocholines.

Akt is activated in most human cancers and contributes to cell growth, proliferation and cellular survival pathway. Accordingly, it is an attractive target for anticancer therapy. A series of novel alkylphosphocholines, incorporating cyclopentanecarboxylate in the phospholipid head group with trans and cis orientations, were synthesized and evaluated for their Akt phosphorylation inhibitory activities and cytotoxicities against human cancer cell lines, A549, MCF-7 and KATO III. Among the synthesized compounds, 5a, 5b and 6c exhibited potent inhibitory Akt phosphorylation effects with IC50 value of 3.1, 2.0 and 3.0 µM, respectively, and their potencies were better than those of three reference compounds miltefosine, perifosine and edelfosine. All the new compounds, except 5d and 6e, displayed more potent growth inhibition against A549 cells than reference compounds. Specifically, compound 5b exhibited most remarkable cytotoxicities on A549 cells as well as MCF-7 and KATO III cells. Importantly, the cytotoxic effects of these compounds correlated with their Akt phosphorylation inhibitory activities.

Synthesis and biological evaluation of cyclopentane-linked alkyl phosphocholines as potential anticancer agents that act by inhibiting Akt phosphorylation.

Three new series of novel alkylphosphocholine (APC) derivatives containing a cyclopentane ring near the phosphocholine head group were synthesized. In the first set of analogues, the phosphocholine head group was attached to the secondary alcohol of trans-2-(hydroxymethyl)cyclopentanol, whereas in the second and third sets of analogues, the phosphocholine head group was linked to the primary alcohol of trans- and cis-2-(hydroxymethyl)cyclopentanol, respectively. Of the compounds synthesized, compound 6d most potently inhibited Akt phosphorylation with an IC(50) value of 3.6 µM, its potency was greater than the reference compounds miltefosine, perifosine, and erufosine. Compounds 6b and 6d exhibited the most potent growth-inhibitory effects on A549, MCF-7, and KATO-III human cancer cell lines. These compounds also showed more active anti-proliferative effects than the reference compounds. Importantly, the cytotoxic effects of these compounds on A549 cell line were proportional to their abilities to inhibit Akt phosphorylation, which supports that these synthesized APC compounds are novel inhibitors of the Akt cell survival pathway.