Synthesis and antiproliferative potency of 9-beta-D-arabinofuranosyl-2-fluoroadenine phospholipid adducts.

Three novel alkylphospholipid and four novel O-alkylglycerophospholipid derivatives of fludarabine (F-ara-AMP), known as a drug for the clinical treatment of chronic lymphocytic leukemia, were synthesized. The antiproliferative activity was determined in comparison to the parent nucleoside fludarabine in an immortalized but nontumorigenic human mammary epithelial cell line (H 184 A1N4), in two human breast tumor cell lines (MaTu and MCF7), and in two leukemic cell lines (HL 60 and Daudi). Fludarabine inhibited the growth of the leucemic cell lines very effectively.

Opposite effects on cytosolic Ca2+ of antitumor phospholipids by induction of calcium influx and activation of endoplasmic reticulum Ca(2+)-ATPase.

The ability of four different antitumor phospholipids, 1-O-hexadecyl-2-chloro-2-deoxyglycero-3-phosphocholine (ET16CIPC), hexadecylphosphocholine (C16OPC), hexadecylphospho-L-serine analogs (C16OPS, C16OPS-N-Ac) and cytidine-5'-hexadecylphosphonophosphate (C16PCMP) to modulate the cytosolic Ca2+ concentration [Ca2+]i was studied in an immortalized human mammary epithelial cell line H184 A1N4. The compounds induced different modes of activity depending on their structure and concentration. ET16CIPC induced between 0.

1-beta-D-Arabinofuranosylcytosine-5'-alkylphosphonophosphates and diphosphates: new orally active derivatives of ara-C.

ara-Cytidine-5'-alkylphosphonophosphates and the corresponding -diphosphates were found to be cytostatically active in vitro against the human mammary epithelial cell line H184 A1N4 and the human mammary tumor cell line MaTu. Our results indicate that the replacement of the diphosphate by the phosphonophosphate group has no influence on antiproliferative activity in this case. The compounds were more active than the corresponding cytidine phospholipid conjugates and related compounds lacking a cytostatically active nucleoside, the ara-C prodrug Cytoros, and were slightly less active than ara-C.

New nucleoside-5'-alkylphosphonophosphates and related compounds containing 2'-deoxycytidine, thymidine and adenosine as nucleoside component. Syntheses and their effects on tumor cell growth in vitro.

Recent studies have shown that phosphono analogs of cytidine-5'-diphosphate diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety exhibit antiproliferative activity in vitro. As an extension of our previous work we tried to elucidate whether the presence of the cytidine component is necessary for cytostatic activity. In this context we have synthesized similarly structured nucleoside-phospholipid conjugates containing nucleoside components other than cytidine, which also do not exhibit cytostatic properties as such.

Modulation of the cytosolic Ca++ concentration by alkylphospho-L-serine analogs: relation to their antiproliferative action.

Antiproliferative alkyllysophospholipid (ALP) analogs produced multiple effects on the cytosolic Ca++ concentration ([Ca++]i) in an immortalized human breast epithelial cell line (H 184). The addition of small concentrations resulted in a short transient [Ca++]i response. With higher concentrations the transient rise was followed by a sustained increase.

Synthesis and antiproliferative activity of cytidine-5'-alkylphosphonophosphates and structurally related compounds.

The chemical synthesis of cytidine-5'-alkyl- and cytidine-5'-alkyl (acyl)deoxyglycerophosphonophosphates is reported. The compounds obtained represent a novel class of cytostatically active agents based on phospholipids, which inhibit the growth of various tumor cell lines in vitro. They are phosphono analogs of the cytidine-5'-diphosphate-diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety and a phospholipase C-resistant P-C bond.

Cellular signalling as a target in cancer chemotherapy. Phospholipid analogues as inhibitors of mitogenic signal transduction.

Mitogenic signalling mechanisms emerged as novel targets for tumor chemotherapy. Current strategies for pharmacological interventions are briefly discussed. Phospholipid analogues are treated in greater detail.

Interference of new alkylphospholipid analogues with mitogenic signal transduction.

The interference of several new hexadecylphosphocholine analogues with mitogenic signal transduction was investigated in NIH3T3 fibroblasts by studying the effects of these agents on thrombin-induced inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation and the subsequent Ca2+ release, on protein kinase C (PKC) in cell-free extracts, on the PKC-mediated activation of the Na+/H+ antiporter and on c-fos induction. The compounds investigated include hexadecylphosphocholine (HePC), octadecyl-[2-(N-methyl-piperidinio)-ethyl]-phosphate (D20133), octadecyl-(N,N-dimethyl-piperidinio-4-yl)-phosphate (D21266); octadecyl-[2-(trimethyl-arsonio)-ethyl]-phosphate (D21805) and hexadecylphospho-L-serine (HePS). The data indicate that (i) all compounds inhibit the thrombin-induced progression of growth-arrested NIH3T3 cells into S phase with similar IC50 values; (ii) the common denominator of all compounds is a reduction of Ins(1,4,5)P3 formation, resulting in an attenuation of Ca2+ release; (iii) the direct interaction with PKC does not significantly contribute to the antitumor activity of these agents; (iv) the new HePC congeners D21266, D21133 and D21805 affect the same targets as HePC, i.

Analogs of alkyllysophospholipids: chemistry, effects on the molecular level and their consequences for normal and malignant cells.

In the search for new approaches to cancer therapy, the first alkyllysophospholipid (ALP) analogs were designed and studied about two decades ago, either as potential immunomodulators or as antimetabolites of phospholipid metabolism. In the meantime, it has been demonstrated that they really act in this way. However, their special importance is based on the fact that, in addition, they interfere with key events of signal transduction, such as hormone (or cytokine)-receptor binding or processing, protein kinase C or phospholipase C function and phosphatidylinositol and calcium metabolism.

Effect of ALP analogs on inositol trisphosphate formation in H184 mammary epithelial cells before and after transfection with v-erb B oncogene.

The influence of cytostatically active alkyllysophospholipid analogs with different chemical structure on IP3 (inositol-1,4,5-trisphosphate) formation and intracellular Ca++ concentration was studied in human mammary epithelial cells before and after transfection with v-erb B oncogene DNA. Transformed cells showed an increased IP3 formation compared with normal cells. In the presence of ALP (alkyllysophospholipid) analogs IP3 formation is inhibited more strongly in transformed cells than in normal cells, dependent on the structure of ALP analogs.

Multiple effects of antitumor alkyl-lysophospholipid analogs on the cytosolic free Ca2+ concentration in a normal and a breast cancer cell line.

Synthetic alkyl-lysophospholipids (ALP) are a new class of antitumor agents which interact with the cell membrane and the intracellular signal transduction at several sites. We studied the modulation of the intracellular calcium concentration ([Ca++]i) induced by two alkylglycerophosphocholines as well as hexadecylphosphocholine and hexadecylphosphoserine in a nontumorigenic and in a tumorigenic breast cell line. We found three distinct [Ca++]i-modulating effects: a transient increase, a decrease and a sustained increase.

Cytostatic effects of various alkyl phospholipid analogues on different cells in vitro.

Phospholipid analogues were studied with regard to their cytostatic activity on different tumour cell lines and on murine bone marrow cells. Compounds compared for their activity were alkylglycero- and alkyl-phosphocholines with the corresponding serines and the alkylphosphocholines and -serines with the corresponding phosphono derivatives. Moreover, compounds containing cytidine 5'-diphosphate instead of the phospho (or phosphono-) choline or serine moiety were studied.

Alteration of DNA topoisomerase II activity during infection of H9 cells by human immunodeficiency virus type 1 in vitro: a target for potential therapeutic agents.

Infection of H9 cells with human immunodeficiency virus type 1 (HIV-1) was found to decrease the phosphorylation of DNA topoisomerase II during the initial phase of infection. Simultaneously, with a later overshoot of phosphorylation and the subsequent activation of DNA topoisomerase II, the production of HIV-1 started. Applying three new protein kinase C inhibitors from the class of O-alkylglycerophospholipids we demonstrated that inhibition of protein kinase C-mediated phosphorylation of DNA topoisomerase II resulted in an inhibition of HIV-1 production.

Halo lipids. 10. Synthesis and cytostatic activity of O-alkylglycerophospho-L-serine analogs.

The synthesis of O-alkylglycerophospho-L-serine analogs is described, which represent a new class of cytostatically active agents based on phospholipids. The new compounds were obtained by conversion of O-alkylglycerophosphoric ester analogs by means of phospholipase D and by condensing O-alkylglycerophosphoric acid analogs with protected L-serine followed by the removal of protective groups of the resulting intermediates. The structure of the O-alkylglycerophospho-L-serines was confirmed by fast atom bombardment mass spectrometry.

Toxic effects of alkyl-lysophospholipids on human bone marrow and de novo leukaemias. A short overview.

Alkyl-lysophospholipids (ALPs) are reported to have an antineoplastic activity against leukaemic cells. We have tested some halogen-containing ALPs from the Central Institute of Molecular Biology (H. Brachwitz) in comparison with racemic 1-ostadecyl-2-methyl-glycero-3-phosphocholine (ET-18-OCH3) (P.

[The effect of alkyl-lysophospholipids and membrane potentials, proliferation and migration of isolated calf aorta endothelial cells].

Cancerostatical active synthetic alkyl-lysophospholipids were examined with regard to their effects on membrane potential, proliferation and migration of isolated endothelial cells. In sublytic concentrations all alkyl-lysophospholipids tested caused a hyperpolarization of the membrane of endothelial cells. The effect of alkyl-lysophospholipids on proliferation of endothelial cells was dependent on the serum supplement.

Cytostatic activity of synthetic O-alkylglycerolipids.

A series of halogen-containing alkylglycerolipid analogs has been checked for their cytostatic activity both in vitro and in vivo. The compounds included alkyldeoxyhaloglycerols (I), alkyldeoxyhaloglycerophosphocholines (II), and alkyldeoxyhaloglycerophosphoric acids and alkyl esters (III). While compounds I and III were moderately active, compounds II were found to have a strong inhibitory effect on the proliferation of Ehrlich ascites tumor cells in vitro.

Halo lipids. VI. Stimulation of human and rabbit blood platelets by racemic halo analogues of O-alkyl-glycerophosphocholine.

Halo analogues of O-alkyl- glycerophosphocholines are shown to stimulate human and rabbit blood platelets. Using 50-500 microM, a concentration dependent platelet aggregation is triggered in human platelet-rich plasma. Distinctly lower concentrations up to 10 microM activate the platelets in rabbit platelet-rich plasma.

Inhibition of proliferation of Ehrlich ascites carcinoma cells in vitro and in vivo by halogeno analogues of long chain acyl- and alkylglycerols.

A series of halogeno (chloro or fluoro) analogues of phospholipid precursors has been checked for their cytostatic activity both in vitro and in vivo. The compounds included monoacyl-, diacyl-, monoalkyldeoxyhalogenoglycerols and other acylhalogenoalkanols. Analogues of monoacylglycerols or monoalkylglycerols were found to have a strong inhibitory activity on the proliferation of Ehrlich ascites carcinoma cells in suspension culture.