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A quantitative structure–activity relationship (QSAR) study was carried out on 112 anticancer compounds to develop a robust model for the prediction of anti-leukemia activity (pGI 50 ) against MOLT-4 and P388 leukemia cell lines. The Genetic algorithm (GA) and multiple linear regression analysis (MLRA) were used to select the descriptors and to generate the correlation models that relate the structural features to the biological activities. The final equations consist of 15 and 10 molecular descriptors calculated using the paDEL molecular descriptor software. The GA-MLRA analysis showed that the Conventional bond order ID number of order 1 (piPC1), number of atomic composition (nAtomic), and Largest absolute eigenvalue of Burden modified matrix – n 7/weighted by relative mass (SpMax7_Bhm) play a significant role in predicting the anticancer activities of these compounds. The best QSAR model for MOLT-4 was obtained with R 2 value of 0.902, Q 2 LOO = 0.881 and R 2 pred = 0.635, while for P388 cell line R 2 = 0.904, Q 2 LOO = 0.856 and R 2 pred = 0.670. The Y-scrambling/randomization validation also confirms the statistical significance of the models. These models are expected to be useful for predicting the inhibitory activity (pGI50) against MOLT-4 and P388 leukemia cell lines.

Four polyacetylenes related to petroformyne-1 were isolated from the marine sponge Petrosia sp. Their structures were determined on the basis of spectroscopic data and the modified Mosher analysis. They exhibit cytotoxic activity against P388 murine leukemia cells.

A series of tricyclic hydroquinones, incorporating a carbonyl group in the ortho position relative to the phenol function, were tested as inhibitors of oxygen uptake against the TA3 mouse carcinoma cell line and its multidrug-resistant variant TA3-MTX-R. The title compound, which proved to be the most active one, also exhibited low micromolar dose-dependent growth inhibition of the human tumor U937 cell line (human monocytic leukemia). A tentative structure-activity relationship is proposed for these substances. A comparison between the cytotoxicities of the title compound and 4,4-dimethyl-5,8-dihydroxynaphthalene-1-one, with their activities as inhibitors of oxygen uptake by the TA3-MTX-R cell line, is presented. Also, the inhibition of oxygen uptake by 6-(4-methylpent-3-enyl)-1,4-naphthoquinone was determined and compared with its reported cytotoxicity toward P-388 (murine lymphocytic leukemia), A-549 (human lung carcinoma), HT-29 (human colon carcinoma), and MEL-28 (human melanoma) cells. The inhibition of oxygen uptake by TA3-MTX-R cells is useful as a quick test for preliminary screening of possible anticancer activity.

(−)-4-Aza-4-deoxypodophyllotoxin ( 4 ) was synthesized from (−)-podophyllotoxin ( 1 ) through C-ring cleavage, Curtius rearrangement and intramolecular N -alkylation. Analogue 4 showed potent cytotoxicity against P388 leukemia cells.

Summary Five derivatives of melphalan (( S )-4-[bis(2-chloroethyl)amino]phenylalanine), an alkylating agent presently employed as an antineoplastic in humans, were designed and synthesised as potential prodrugs. Their antitumour activity was tested against P388 leukaemia in mouse after acute intraperitoneal or oral administration and compared with that of the parent compound.

A novel natural sesquiterpene–dimer-type compound, named parviflorene A ( 1 ), was isolated from the extract of a tropical Zingiberaceous plant, Curcuma parviflora, collected in Thailand, and its structure was elucidated by spectral data. Parviflorene A ( 1 ) possesses an unprecedented unsymmetrical bis-cadinane skeleton and exhibited cytotoxic activity against murine leukemia P388 and B16 melanoma cells.

The A ring of the clinical antitumor agent, etoposide, was opened to a protected 6,7-diphenol which was derivatized to form a number of new analogs. These compounds displayed activity inferior to etoposide when evaluated against several tumor cells line in vitro and against murine P388 leukemia in vivo .

The typical MDR phenotype have been associated, among other signs, with reduced intracellular accumulation of MDR-causing drugs. We have studied the rubomicin (rub) and adriablastin (adr) accumulation by the fluorescent spectroscopy method. We have chosen, from our laboratory collection of P388 leukemia MDR-strains, vinblastine-resistant tumor (P388/vbl) possessed by MDR1 gene amplification and cross restistance to MDR causing drug and adriablastin-resistant tumor (P388/adr1) having incomplete pattern of cross resistance and no MDR1 gene amplification. There were moderate but constant differences in drugs accumulation between cells of sensitive and resistant strains. The rub and adr accumulation by P388/adrl cells was 2.1 and 1.3 times less than that observed in sensitive cells. These finding were I. 7 and 1. 3 for P388/vbl respectively. There were no differences of the parameter between resistant strains. Taken together the data suggest that several different mechanisms could participate even in case of classic MDR.

The scope of the structure-anticancer activity relationship among various aliphatic and aromatic hydrazones containing the N,N,N′,N′ -bis(1,2-ethanediyl)-phosphoric diamide moiety was studied. A total of 19 compounds were tested in vivo, using murine lymphocytic leukemia P388. At optimum dose all these compounds were active. The highest activity was exhibited by the N,N;N′,N′ -bis(1,2-ethanediyl)-[ N 2 -( p -chlorobenzylidene)- N 1 -hydrazin-1-yl]phosphoric triamide, N,N;N′,N′ -bis(1,2-ethanediyl)- N 2 -( p -chlorobenzylidene)- N 1 -methyl-hydrazin-1-yl]phosphoric triamide and N,N;N′,N′ -bis(1,2-ethanediyl)-[ N 2 -( p -chlorobenzylidene)- N 1 -phenylhydrazin-1-yl]phosphoric triamide as is evidenced by the percent T/C of 212, 194 and 192, respectively. An attempt was made to correlate the anticancer activities with the corresponding lipophilicities. On the basis of the activity-lipophilicity results, it is concluded that, in general, the activity scale follows the lipophilicity scale in the reverse order, i.e. the more active compounds possess lower lipophilicity than the less active compounds.

Conformational analysis of 2-[bis-(2-chloroethyl)amino]-2-trans-tetramethylene-1,3,2-dioxa- and oxazaphosphorinanes 5–8, cyclophosphamide-type anticancer drugs, show that diastereometric six-membered ring 1,3,2-dioxaphosphor- inanes can adopt either a chair conformation with bis-(2-chloroethyl)amino mustard group equatorial (5) or twist-boat conformation with the bis-(2-chloroethyl)amino group pseudoequatorial (6). An X-ray crystal structure and NMR solution conformational analysis of the diastereomeric oxazaphosphorinanes 7 and 8 show that 7 adopts a chair conformation with equatorial bis-(2-chloroethyl)amino group, and 8 exists as mixture of chair-twist boat conformations with ca. 50% twist boat population. The diastereomeric pairs 5 6 and 7 8 show similar, moderate activity against lymphocytic leukemia P388 cells in mice. This is explained in terms of a flexible chair-twist boat interconversion.

Summary As a follow-up to our initial results on the antineoplastic activity of α-1,3,5-triglyciyl-s-triazinetrione (αTGT, NSC-296934, Teroxirone), many new epoxyde derivatives were tested against murine tumours, mostly against P388 leukemia, to determnie their anti-neoplastic role and to characterize their specific effect against tumour cells in vivo , as well as to select an analogue with higher anti-cancer properties and superior pharmacological properties. triglycidyl urazol (TGU, NSC-332488) showed the highest therapeutic activity and a good level of water-solubility which makes this agent a good candidate for phase-one clinical trials.

The study comprised mice of BDF1 hybrides, i.e. cross-breds F1/C57BL/6 X DBA/2, sires, aged 3 months, injected peritoneally with lymphatic leukemia P 388 in the amount of 10(4) cells. The mice were killed 5 or 11 days after injection. Peroxisomes were examined in the liver. Therefore, cytoenzymatic studies were conducted to determine the catalase activity. It was found that, after initial increase of activity (5th day of the experiment) a total or nearly total lack of catalase occurred in leukemic lymphocytes after 11 days of the disease. This was accompanied by gradual vanishing of peroxisomes-catalase transfer. It was also found that free radicals participated actively in the destabilisation of biological membranes by damaging cellular peroxisomes.

A series of diorganotin(IV) derivatives of bis(carboxymethyl)amine and its N-methyl derivative have been prepared, characterized by NMR, Mossbauer and mass spectrometry and tested in vivo against P388 leukemia.

Some new di-n-butyltin and tin(IV) complexes of the type Bu2SnL, Bu2SnL2 and SnL2 (where L = anions of Schiff bases derived from S-substituted dithiocarbazates and fluoro-aniline) have been prepared and screened for their antitumor activity in P 388 Lymphocyte Leukaemia system. These complexes do not show any toxicity at low dose levels and display T/C values in the range 94-124. Di-n-butyltin complex derived from salicylaldehyde-S-methyl dithiocarbazate has been found to be the most active in this series.

Various structural types of nogalamycin congeners and their partial structures, which had been previously synthesized in the course of our synthetic studies on the total syntheses or were originally produced by employing the explored synthetic scheme, were subjected to in vitro cytotoxicity and in vivo antitumor activity assay against P388 munne leukemia. These studies obviously disclosed novel aspects of the structure-activity relationships of nogalamycin congeners.

Complexes of Fe(II), Co(II), Ni(II), Cu(II), Cd(II), Pd(II), Pt(II) and Zn(II) with the anti-tumor agent 2,2′-bipyridyl-6-carbothioamide ( bpyta, 1 ) were prepared and characterized. All these metal(II) complexes were screened for their cytostatic activities in vitro against murine P388 leukemia. The copper(II) complex 2f was found to be 12-fold more active than ligand 1. bpyta and its complexes were also evaluated for their anti-fungal activities. Some of the studied complexes displayed significant anti-fungal activity which, however, was lower than that of the parent ligand.

A series of enantiomeric cisplatin analogues of formula [diamPtCl2] (diam = chiral chelating diamine) and the corresponding sulfato derivatives was prepared and tested for activity against tumors in mice, particularly P 388 leukemia. The configuration of the diamines has practically no influence on the antitumor activity. The effects of the leaving group and of the nature of the diamines are briefly discussed.

The paper reports the synthesis, the chemical characterization and the IR data of new Pt(II) and Pt(IV) complexes, as well as their cytostatic activities on KB cells and antitumour properties against three tumour systems (P388 and L1210 leukemias and advanced B16 melanoma). The following ligands were used: 2,5-dichloroaniline, 3,4-dichloroaniline, 2,4,6-trichloroaniline, 3,4,5-trichloroaniline, 2,3,4,5-tetrachloroaniline and 2,3,5,6-tetrachloroaniline. The tri- and tetrachloroaniline-Pt(II) complexes displayed a fairly good antileukemic activity but lower than cisplatin. The effect of these compounds against advanced B16 melanoma appears more interesting. They show an activity comparable or in some cases higher than cisplatin and other 1,2-diaminocyclohexane-Pt(II) complexes. The M.O. Huckel's calculations were performed on the ligand molecules in order to help us to draw a structure-activity relationship for new compounds.

A subline of P388 lymphocytic leukemia resistant to 4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) was obtained by serial i.p. passage of tumor cells in mice treated i.p. with m-AMSA. Partial resistance was evident following eleven transplant generations. Complete resistance to m-AMSA (

The combined effects of fractionated administration of the antiviral agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and fractionated (4 injections at a 48-h interval) administration or continuous (7-day) infusion of 5-fluorouracil (FU) have been investigated in P388 leukemia-bearing mice. The LD50 of continuous FU infusion in normal mice was approximately 330 mg/kg, while that for the fractionated treatment was 160 mg/kg. When combined with BVDU (200 mumol/kg, 90 min before each FU injection; 4 injections at a 48-h interval), the LD50 of FU was decreased from 330 to 115 mg/kg and from 160 to 30 mg/kg, respectively. The 7-day continuous infusion of FU (up to a dose of 210 mg/kg) did not exert a therapeutic effect in P388-leukemic mice, and, similarly, combination of continuous FU infusion (at lower doses) with BVDU failed to increase the survival of the leukemic mice. If, however, FU was administered in fractionated doses, there was a dose-dependent increase in survival time of P388-leukemic mice, and simultaneous fractionated BVDU treatment allowed a 4-6-fold lower dose of FU to achieve the same increase in survival time, indicating that BVDU effectively increased the antitumor activity of FU in the leukemic mice.

Complexes of Co(Il), Ni(II), Cu(II), Zn(II) and Pt(II) with 4-( m -aminophenyl)-2-formylpyridine thiosemicarbazone (4- m -NH 2 ph-2-pytsc-H) were isolated and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature to liquid N 2 temperature), diffuse reflectance and infrared studies. On the basis of these studies a distorted trigonal-bipyramidal structure for [M(4- m -NH 2 ph-2-pytsc-H)Cl 2 ] (M = Co(II), Ni(II) or Cu(II)), [Zn(4- m -NH 2 ph-2-pytsc-H)(OAc) 2 ] and a square-planar structure for [Pt(4- m -NH 2 ph-2- pytsc)Cl] are suggested. All these metal(II) chelates were screened for their antitumour activity in the P388 lymphocytic leukaemia test system in mice, and were found to possess no significant activity at the dosages employed.

cis -5-Hydroxy-4-(4′-hydroxy-3′-methoxyphenyl)-4-(2″-imidazolyl)-1,2,3-trithiane 1 was isolated from the New Zealand ascidian Aplidium sp. D. In neutral or slightly basic solution 1 interconverts to the trans isomer 3 . These isomers are the precursors to 2-vanilloyl imidazole 2 , previously reported from an extract of an Australian species of Aplidium . Both trithiane isomers are active against P388 leukemia cells in vitro .

The antitumor effect of dicyclohexylammonium sulfate (DCHA), a potent inhibitor of spermidine synthase, was tested on BDF1 mice inoculated i.p. with P388 leukemia (1 × 106 cells/mouse). DCHA prolonged the survival time of mice bearing P388 leukemia at the doses of 10–100 mg/kg administered daily for 6 days. The spleen weight increased by 30% at 7 days after tumor inoculation. DCHA treatment had no effect on the tumor-induced increase in splenic weight. The spermidine concentration of the ascites tumor cells and spleens of mice bearing the tumor was lowered by the treatment, while spermine concentration hardly changed. The depletion of spermidine in the ascites tumor cells and spleens might be a cause of the suppression of tumor growth.

Cunninghamella elegans (NRRL 1393) transformed 2,3-dihydro-3-methoxywithaferin-A to 2,3-dihydro-12β-hydroxy-3-methoxywithaferin-A. Both compounds inhibited the growth and biochemical functions of in vitro grown P388 lympholeukemic cells.

A calcium antagonist, verapamil, enhanced the cellular uptake and cytotoxicity of vincristine (VCR) in adriamycin-resistant P388 leukemia (P388/ADM) cells and also enhanced the cellular uptake and cytotoxicity of adriamycin (ADM) in vincristine-resistant P388 leukemia (P388/VCR) and P388/ADM cells. The enhancement of cytotoxicity and cellular uptake of VCR in P388 and P388/VCR cells has been reported previously. [1]. VCR and ADM resistance was circumvented by verapamil. A common transport mechanism for VCR and ADM, which is responsive to verapamil, seems to exist in VCR- and ADM-resistant cells. However, the enhancement of ADM cytotoxicity and cellular uptake by verapamil was not evident in P388 cells.

AC-3579 (NSC-170561), a diazafluoranthen derivative, was given intraperitoneally (100 to 300 mg/kg per day) to BDF1 mice with P388 or L1210 leukemia from day 1 to 9 or until death. Its administration produced an increase of the survival time over the controls of 44 to 66% in P388 and 23 to 28% in L1210. A 5-day administration of the drug (100 mg/kg per day) resulted in a 3-fold decrease of the number of cells per ascites. Electron microscopic examination of cells remaining in the peritoneal cavity after the treatment failed to demonstrate any striking modification. Biochemical determination showed a 70% increase of total cellular phospholipids and a marked enhancement of [32P]-orthophosphate incorporation into total phospholipids. Specific activities of ATPase and 5′AMPase as well as the labeling index with tritiated thymidine were not affected by the treatment in vivo. Both morphologic and chemical data indicated that the antitumor action of AC-3579 could differ from its effect on rat hepatocytes which has been previously elucidated.