DNA-directed alkylating agents. 5. Acridinecarboxamide derivatives of (1,2-diaminoethane)dichloroplatinum(II).

A series of acridine-2- and -4-carboxamide-linked analogues of PtenCl2 has been prepared and evaluated for biological activity against several tumor cell lines in vitro and in vivo. The platinum complexes were generally more cytotoxic than the corresponding ligands against wild-type P388 leukemia cells in vitro, with acridine-4-carboxamide complexes being the more effective. In contrast to cisplatin and PtenCl2, the complexes were equally active in vitro against both wild-type and cisplatin-resistant P388 lines. The 4-carboxamide complexes showed high levels of in vivo activity (ILS greater than 100%) against wild-type P388 using a single-dose protocol, and one compound was also significantly active in vivo in a cisplatin-resistant line, against which cisplatin and PtenCl2 are inactive.     

Antitumor properties of 2(1H)-pyrimidinone riboside (zebularine) and its fluorinated analogues

2(1H)-Pyrimidinone riboside (zebularine, 1b) and its 5-fluoro (6b) and 2'-ara-fluoro (7b) analogues have been synthesized and evaluated in vivo as antitumor agents. Zebularine provides increase in life span (ILS) values of ca. 70% against intraperitoneal (ip) murine B16 melanoma and 50% against P388 leukemia. This compound is active when administered either ip or orally against ip or subcutaneously implanted L1210 leukemia, producing ILS values of about 100% at an optimum dose of 400 mg/kg. 1b is also active (60% ILS) against ara-C-resistant L1210. The analogous unsubstituted purine riboside nebularine (2) has modest activity against P388 leukemia (60% ILS). While 2'-ara-fluorozebularine (7b) is only marginally active (40% ILS) at high doses against L1210 leukemia, 5-fluoro analogue 6b is more active than zebularine and is ca. 100 times more potent. Although the activity of 6b is about the same as that of 1b against P388 leukemia, greater potency also is realized in this model. Zebularine is a strong inhibitor of cytidine deaminase, but in contrast to tetrahydrouridine, 1b is acid-stable. In an attempt to use this property to advantage in oral administration, 1b and ara-C have been orally coadministered to mice with ip L1210 leukemia. When zebularine is given in divided doses, up to a 2-fold increase in activity is realized, relative to treatment with the same dose of ara-C alone.     

Hypoxia-selective nitrobenzyloxycarbonyl derivatives of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines

Some 4- and 2-(nitrobenzyloxycarbonyl)-1, 2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines (4, 6, and 7) were synthesized and evaluated for their ability to exert preferential toxicity to hypoxic EMT6 mammary carcinoma cells using a colony-forming assay. Of these, the 4,5-dimethoxy-2-nitro analogue 6 (50 microM, 1-h exposure) caused greater than 3 logs of kill of hypoxic cells, with relatively minor toxicity to corresponding aerobic cells. The ability of 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues to reach and kill hypoxic cells of solid tumors was also demonstrated using intradermally implanted EMT6 solid tumors in mice. In addition, a possible source of toxicity to normal tissue, i. e., the activation of the 4-nitrobenzyl derivative 4 by glutathione S-transferase-catalyzed thiolysis, was essentially eliminated by replacing one of the benzylic methylene protons by a methyl group. The 4-nitro (4) and 4,5-dimethoxy-2-nitro (6) analogues also appear to be reduced more easily under acidic conditions (pH 6.0) than under neutral conditions, as measured by differential pulse polarography. Since the pH in hypoxic regions is often lower than that in adjacent aerobic regions, this property should aid in the cytotoxic action of these agents against hypoxic cells of solid tumors.     

New 2-substituted indoloquinone mitomycin analogues

Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been too reactive chemically for selective alkylation of DNA, we prepared new analogues with substituents that could give variation in the reduction potential of the quinone ring, which might control their rate of bioactivation. The 5-methoxyindoloquinones were much more potent cytotoxics than mitomycin C against human tumor cell lines, but they were inactive against P388 leukemia in mice. Two 5-aziridinylindoloquinones were also more potent than mitomycin C against the cell lines and one of them was active in the P388 model upon in vivo assay. The corresponding 5-amino analogues were less potent than mitomycin C against both the cell lines and murine P388 leukemia. A 2-(1-hydroxyethyl)carbamate was prepared by a 20-step synthesis. It was about one-fourth as potent as mitomycin C against two cell lines.     

Synthesis, chemical reactivity, and antileukemic activity of 5-substituted 6,7-bis(hydroxymethyl)pyrrolo[1,2-c]thiazole biscarbamates and the corresponding sulfoxides and sulfones

A series of bis(N-methylcarbamate) and bis[N-(2-propyl)carbamate] derivatives of 5-substituted 6,7-bis(hydroxy-methyl)pyrrolo[1,2-c]thiazoles was prepared. The compounds were tested for activity in vivo against P388 lymphocytic leukemia, and the chemical reactivities of the compounds were compared by using the model nucleophile 4-(4-nitrobenzyl)pyridine (NBP). The 5-(3,4-dichlorophenyl)-substituted biscarbamates 6b, 8b, and 12b were inactive and unreactive toward NBP. The 5-methyl-substituted biscarbamates 6a, 7a, 8a, 9a, 12a, and 13a were all active against murine P388 lymphocytic leukemia. The chemical reactivities of the active compounds depended on the oxidation state of the sulfur. The reactivity toward NBP followed the order S greater than SO much greater than SO2. The sulfones 12a and 13a are the most active compounds in this series, and their lack of reactivity toward NBP led to the suggestion that 12a and 13a are activated in vivo.     

Synthesis and evaluation of 1,2,2-tris(sulfonyl)hydrazines as antineoplastic and trypanocidal agents

Several 1,2,2-tris(sulfonyl)hydrazines, conceived as prodrugs of 1,2-bis(sulfonyl)hydrazines, were synthesized and evaluated for antineoplastic and trypanocidal activities in mice. 1-Methyl-1,2,2-tris(methylsulfonyl)hydrazine emerged as an extremely efficacious antitrypanosomal agent, whereas 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine was inactive. In contrast, 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine displayed potent antineoplastic activity, producing several 60-day "cures" of mice bearing leukemia L1210, leukemia P388, or Sarcoma 180. Furthermore, the fact that the tris(sulfonyl) derivatives will not generate isocyanates, which contribute to the host toxicity of nitrosoureas like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), makes them agents of significant promise in trypanosomal and cancer chemotherapy.     

Compounds with presumable antitumor activity. II. 2-Substituted 3-(2-thiazolyl) and 3-[2-(1,3,4,-thiadizolyl)]-4-thiazolidinones

2-Substituted 3-(2-thiazolyl) and 3-[2-(1,3,4-thiadiazolyl)]-4-thiazolidinones were prepared and tested for their activity against the leukemic P 388 tumor system in mice. The thiadiazolyl derivatives are generally more active than the thiazolyl ones and some of them showed significant activity.     

Synthesis and antitumor activity of fused tetracyclic quinoline derivatives. 1

Several fused tri- and tetracyclic quinolines (I and II) with [2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino or [3-(N,N-dimethylamino)propyl]amino side chains were prepared, and their DNA intercalative properties, KB cytotoxicity, antitumor activity (P388 leukemia), and ability to induce topoisomerase II dependent DNA cleavage were investigated. Some compounds having both intercalative ability and KB cytotoxicity were found to be inactive in vivo. However, a positive correlation was seen between the ability to induce topoisomerase II dependent DNA cleavage and antitumor activity in vivo. The indeno- (13a), benzofuro- (21a), and benzothieno- (22a) quinoline derivatives exhibited potent antitumor activities in vitro and in vivo, comparable to those of m-AMSA. They also intercalate DNA and induce topoisomerase II dependent DNA cleavage. Extended screening of 13a showed it to be active against solid tumors such as M5076 sarcoma, B16 melanoma, and colon 38 carcinoma.     

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.     

Synthesis and evaluation of antitumor activity of novel 1,4-Naphthoquinone derivatives (IV)

1,4-Naphthoquinones are widely distributed in nature and many clinically important antitumor drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and saintopin, show excellent anticancer activity. In this study, 2- or 6-substituted 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) and 5,8-dihydroxy-1,4-naphthoquinone (DHNQ) derivatives were synthesized, and their cytotoxic activity against L1210 and P388 cancer cells was examined. Their antitumor activity was also assessed in mice bearing S-180 cells in the peritoneal cavity. In comparison with the DMNQ derivatives, the DHNQ derivatives exhibited more potent bioactivities than the DMNQ derivatives against both L1210 and P388 cells in vitro and S-180 cells in vivo. The ED50 values of the DHNQ derivatives against P388 cells were in the range of 0.18-1.81 microg/mL whereas those of the DMNQ derivatives were in the range of 0.26-40.41 microg/mL. The T/C (%) values of the DHNQ derivatives, 8, 17, 18, 19, and 20, were found to be comparable to or even better than that of adriamycin. It was also observed that the 2-substituted derivatives (8, 19, 20) showed better antitumor activity than the 6-substituted derivatives (7, 17, 18) in the mice bearing S-180 cells in the peritoneal cavity.     

Antineoplastic activity of ASTA Z 7557 (NSC-345842, INN mafosfamide) on transplantable murine tumors

Summary The antitumor activity of ASTA Z 7557, a stabilized primary metabolite of cyclophosphamide, was evaluated in comparison with cyclophosphamide (CP) against different rodent tumor systems. At equimolar doses, which corresponded in mg/kg to the optimal doses of each compound, Z 7557 showed a higher therapeutic activity than CP when both drugs were administered intraperitoneally (ip) during 5 consecutive days. The drug remained active against a P388 subline totally resistant to CP, but to a much lesser extent. The ipimplanted B16 melanoma was highly sensitive to 100 and 50 mg/kg administered during 9 consecutive days: an increase in lifespan (ILS) of 244% was produced and 5 mice out of 10 were cured. This treatment administered against Lewis lung carcinoma (LL) transplanted intravenously (iv) induced an ILS of 179% and 3 mice out of 10 survived on day 60. This effect was slightly inferior to that produced by 50 mg/kg of CP, but is balanced by the number of long-term survivors recorded after administration of low doses of Z 7557. When mice bearing the subcutaneously (sc) implanted colon 38 (C38) tumor were treated with 200 mg/kg on days 2 and 9, the tumor growth was inhibited by 83% in comparison to the control mice. The wide range of activity of Z 7557, its stability and its different chemical reactivity as compared to CP appear to justify interest in this activated oxazaphosphorine.     

3-Pyrroline N-oxide bis(carbamate) tumor inhibitors as analogues of indicine N-oxide

The 2,3-bis[[(N-methylcarbamoyl)oxy]methyl]-3-pyrroline 1-oxide 5 was synthesized and tested in the murine P388 lymphocytic leukemia model. The compound showed significant reproducible activity and was more potent than indicine N-oxide. 1-Methyl-2-phenyl-3,4-bis[[(N-2- propylcarbamoyl)oxy]methyl]-3-pyrroline N-oxide (6) was less active than 5, and the 5,5-dimethyl analogue of 6, the pyrroline N-oxide 7, was inactive. The N-oxide 7 cannot be converted to a pyrrole in vivo because of the gem-dimethyl substitution at C-5.     

Antipicornavirus activity of some diaryl methanes and aralkylaminopyridines

Sixteen diarylmethanes and ten aralkylaminopyridines were initially evaluated for their in vitro activity against rhinoviruses 1A, 2 and 64 and against coxsackievirus A21 and for their oral prophylactic and therapeutic activity in mice challenged with coxsackievirus A21. Based on these preliminary studies the diarylmethane (3,4-dichlorophenoxy)-(5 methylsulfonyl-2-pyridinyl)-methane and the aralkylaminopyridine (2-(3,4-dichlorobenzylamino)-5-methylsulfonylpyridine were compared with their oxygen bridged analogue 2-(3,4-dichlorophenoxy)-5-(methylsulfonyl)pyridine for in vitro activity against a larger number of picornaviruses and for their in vivo protective efficacy in dose response assays. All three compounds exhibit similar in vitro activity inhibiting 12 to 15 (52.2-65.3%) of the 23 picornaviruses tested at concentrations of less than 5.0 micrograms/ml. However, the aralkylaminopyridine was found to be the most active in vivo; significantly protecting coxsackievirus A21 challenged mice after a single oral dose of 37.5 mg/kg (P less than or equal to 0.05) and during a continuous oral dose regimen of as low as 18.8 mg/kg per day (P less than 0.01).     

Preparation, characterization, and anticancer activity of a series of cis-PtCl2 complexes linked to anthraquinone intercalators

A new series of complexes of the type cis-PtL2X2 [where L is a monodentate AQ-Y(CH2)nNH2 and L2 is a bidentate AQ-Y(CH2)nNH(CH2)2NH2; AQ = anthraquinone, X = Cl, I, Y = NH, O] in which anthraquinone intercalators are tethered to the cis-PtCl2 unit via an (aminoalkyl)amino, (oxyalkyl)amino, or polyethylene glycol (aminoethyl)amino linker chains was prepared and screened in vitro against P388 leukemia. In vivo toxicity studies were carried out on selected complexes. All complexes were characterized by means of elemental analysis, 195Pt NMR spectroscopy, and FTIR. The 1:1 Pt-intercalator complexes displayed much higher in vitro cytotoxic activities than the 1:2 Pt-intercalator complexes. The dichloride complexes were consistently more active than their diiodide counterparts. Among the 1:1 Pt-intercalator complexes those with the shorter linker chains (n = 2, 3) exhibited the highest cytotoxic activities. Three compounds, [[2-[[2-(anthraquinon-1- ylamino)ethyl]amino]ethyl]amine-N,N']dichloroplatinum(II), [[2-[[3-(anthraquinon-1-ylamino)propyl]amino]ethyl]amine- N,N']dichloroplatinum(II), and [[2-[[3-anthraquinon-1- yloxy)propyl]amino]ethyl]amine-N,N']dichloroplatinum(II), were as active in vitro as cisplatin (ED50 = 2-4 x 10(-7) M) while on a molar basis their acute in vivo toxicity was significantly lower than that of cisplatin. In vivo screening against P388 leukemia indicated that these complexes have activity comparable to cisplatin.     

Pharmacological and toxicological studies on new Rh(I) organometallic complexes.

New rhodium(I) complexes, belonging to the general structure [Rh(CO)2 (L)], where dithiocarbamate and xanthate derivatives, were synthesized and assayed as cytostatic and antitumour agents in vitro against KB cells and in vivo against P388 leukaemia, Ehrlich ascites carcinoma, Sarcoma 180 ascites and ADJ/PC6A solid tumour. Assays against five trypanosoma strains were also performed. Among the new compounds the [Rh(CO)2 (DPA-dtc)] appeared to be active in all biological systems without showing evident nephrotoxicity.     

Synthesis and antitumor activity of sulfur-containing 9-anilinoacridines

A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer potential. Among the compounds, both diol-containing compounds, 2a and 3, were the most cytotoxic of the sulfide series against V-79 cells in vitro (IC(90) = 2.1 microM and 1.9 microM, respectively). Among the non-alkyl-substituted compounds (7-9), compounds with electron-donating substitution para to the sulfide (7 and 9) were more cytotoxic than the electron-withdrawing nitro-substituted compound 8. The limited SAR suggested the importance of hydroxyl functionality along with its location for the cytotoxicity in the series. A preliminary anticancer screening against P388 leukemia showed that 2a is highly active in vivo as well. Topoisomerase II inhibitory activity appeared to be involved in the cytotoxicity of compound 2a. Sulfoxide compound 2b, which is 6-7-fold less cytotoxic than its sulfide 2a, appears to be a potential bioreductive anticancer prodrug on the basis of its bioreductive metabolism findings.     

Comparison of prediction methods for in vivo clearance of (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, a dopamine D2 receptor antagonist, in humans.

The purpose of this study is to investigate reliable prediction methods for in vivo pharmacokinetics and the likelihood of drug interactions with several cytochrome P450 inhibitors in humans for (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (PNU-96391). By allometric scaling of in vivo animal data, clearance of PNU-96391 in humans was over-predicted by 4-fold, half-life was under-predicted by 3-fold, and volume of distribution was accurately predicted. High correlation coefficients (>0.99) were observed for these parameters. Neither the in vitro-in vivo correlation approach nor the modified allometric scaling with maximum life span potential or brain weight accurately provided the predicted clearance value. Using an alternative method, based on normalization of in vitro human data with the ratio of in vivo to in vitro animal data, the in vivo clearance in humans was predicted to be 0.39 l/h/kg. This value correlated well with the in vivo value (0.43 l/h/kg). Regarding the interactions of PNU-96391 with cytochrome P450 inhibitors, only quinidine, haloperidol, and ketoconazole showed significant inhibition on the metabolic clearance of PNU-96391 in human hepatocytes. By comparing in vitro K(i) values with in vivo maximum unbound concentrations of the inhibitor, the increases in systemic exposure of PNU-96391 by coadministration of the inhibitors were estimated to be less than 1.5-fold. A preliminary comparison of pharmacokinetics of PNU-96391 between CYP2D6 extensive and poor metabolizers in the clinical study showed only a slight increase in systemic exposure in poor metabolizers (approximately 1.4-fold as area under the concentration-time curve). Therefore, clinically significant drug-drug interactions of PNU-96391 would be unlikely to occur with coadministration of CYP2D6 inhibitors.     

Biochemical and antitumor activity of tiazofurin and its selenium analog (2-beta-D-ribofuranosyl-4-selenazolecarboxamide)

2-beta-D-Ribofuranosyl-4-selenazolecarboxamide (selenazofurin, CI-935), the selenium analog of tiazofurin (CI-909), was 3- to 10-fold more cytotoxic to murine or human tumor cells in vitro than tiazofurin and was also more active against P388 mouse leukemia in vivo. In vitro cytotoxicity could be reversed by guanosine or guanine but not by other purine nucleosides or bases. Three human tumor cell lines selected for selenazofurin or tiazofurin resistance showed cross resistance between selenazofurin and tiazofurin. Treatment with tiazofurin, selenazofurin, or mycophenolic acid decreased guanylate pools and caused an accumulation of IMP in WIL2 human lymphoma cells. The decrease in guanylate pools was accompanied by inhibition of RNA and DNA synthesis. The NAD analogs of tiazofurin and selenazofurin were inhibitors of L1210 IMP dehydrogenase (IMP:NAD oxidoreductase, EC 1.2.1.14), and both showed uncompetitive inhibition with respect to NAD having Kii values of 5.7 X 10(-8)M and 3.3 X 10(-8)M respectively.     

Anthrapyrazole anticancer agents. Synthesis and structure-activity relationships against murine leukemias

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.     

Synthesis and antitumor activity of a series of ftorafur analogues: the effect of varying electronegativity at the 1'-position

To test the effect of changes in electronegativity within the alicyclic N-1 substituent 5-fluorouracil analogues on cytotoxic activity, a series of derivatives of ftorafur, 1-(2'-tetrahydrofuranyl)-5-fluorouracil, was synthesized and tested for antitumor activity in the P388 lymphocytic leukemia screen and cytotoxic activity in the L1210 cell culture screen. Two compounds of N-1 substituent with high electronegativity, the 2'-tetrahydrothiophene 1'-oxide and the 2'-tetrahydrothiophene 1',1'-dioxide derivatives, demonstrated the highest in vitro L1210 cell inhibition (84.5% and 92.0%, respectively). Furthermore, against P388 lymphocytic leukemia in vivo, the 2'-tetrahydrothiophene 1'-oxide derivative showed significant activity (T/C = 143). Other compounds of similar or lower electronegativity within the N-1 cyclic substituent were inactive against P388 lymphocytic leukemia and less active against L1210 cells.