Synthesis and antitumor evaluation of new thiazolo[5,4-b]quinoline derivatives

A new synthesis of 9-hydroxy- and 9-(alkylamino)thiazolo[5,4-b]quinolines by cyclization of 4-(ethoxycarbonyl)-5-(arylamino)thiazoles and 5-(arylamino)-4-carbamoylthiazoles, respectively, is described. In vitro cytotoxicity of a large number of derivatives of these compounds has been tested against several cell lines. The highest activities observed are associated with the presence of a 2-[[(N,N-diethylamino)ethyl]amino] substituent at C-2 and a fluorine atom at the C-7 position of the tricyclic planar heteroaromatic framework. Three structural features seem to be essential for antitumor activities: a positive charge density at carbon C-7, a side chain at position C-2 or C-9 of the thiazoloquinoline skeleton with two basic nitrogens and a pKa value of 7.5-10 in the most basic center, and a conformational flexibility of this basic side chain. These structural requirements must be simultaneously satisfied in order to ensure a significant antitumor activity.     

Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent

Recently, we reported that 5,4'-diamino-6,8,3'-trifluoroflavone (1b) exhibits potent antitumor activity against certain types of human cancer cell lines both in vitro and in vivo. Since the antiproliferative activity of 5,4'-diaminoflavone (1a), the lead compound of 1b, was modulated by the addition of apigenin, we hypothesized that the 7-position is important for the interaction with a putative target molecule. On the basis of this hypothesis, the structure-activity relationships of the substituents at the 7-position of 1b were explored. As a result, 7-methyl (7a), 7-hydroxymethyl (7l), 7-(acyloxy)methyl (9a,c,e,g,j), and 7-aminomethyl (12f) derivatives were found to exhibit comparable or superior antitumor activity to compound 1b against MCF-7 cells both in vitro and in vivo (po administration). In particular, compounds 9e,g,j, and 12f were sufficiently water-soluble as compared with 1b which hardly solubilizes in water. A lipophilic 7-(hexanoyloxy)methyl derivative (9c) was also found to exhibit strong antitumor activity especially in vivo. Since the modes of action and the target molecule(s) are unknown, a mechanistic study will be important in the future.     

Anthracene-1,4,9,10-tetraone derivatives: synthesis and antitumor activity

A series of 2-alkylated anthracene-1,4,9,10-tetraone (ATO) derivatives were synthesized, and their antitumor action in ICR mice bearing S-180 cells and antiproliferative activity against L1210 cells were evaluated. Overall, the introduction of an alkyl group (C1-C8) at C-2 enhanced the antiproliferative activity. Among 2-(1-hydroxyalkyl)- or 2-(1-acetoxyalkyl)-ATO derivatives, four compounds possessing alkyl chain of an intermediate size (C4-C6) gave T/C values of > 300%. Acetylation at 1'-OH failed to cause an enhancement in the antitumor action, in contrast to a remarkable increase in antiproliferative activity. Although there was no direct relationship between antiproliferative activity and antitumor action, the compounds with lower antiproliferative activity tended to show higher antitumor activity. Further study shows that the antiproliferative activity of ATO derivatives may be explained properly neither by redox cycling nor arylating capacity.     

Naphthazarin derivatives: synthesis, cytotoxic mechanism and evaluation of antitumor activity

Patients with type Ib glycogen storage disease (GSD Ib) are susceptible to hypoglycaemic episodes. To determine whether an amylase (alpha-glucosidase) inhibitor, voglibose, can be useful in the control of hypoglycaemia, we tried it in a 14-y-old male with GSD Ib. Oral administration of voglibose prolonged the duration of normoglycaemia and reduced the incidence of hypoglycaemia attacks. These findings indicate that voglibose may be useful for preventing hypoglycaemia in GSD Ib patients.     

Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme

Endothelin-1 is the most potent peptidic vasoconstrictor discovered to date. The final step of posttranslational processing of this peptide is the conversion of its precursor by endothelin-converting enzyme-1 (ECE-1), a metalloprotease which displays high amino acid sequence identity with neutral endopeptidase 24.11 (NEP) especially at the catalytic center. A series of potent and selective arylacetylene-containing ECE-1 inhibitors have been prepared. (S, S)-3-Cyclohexyl-2-[[5-(2, 4-difluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]amino] propio nic acid (47), an arylacetylene amino phosphonate dipeptide, was found to inhibit ECE-1 and NEP with IC50 values of 14 nM and 2 microM, respectively. Similarly, (S)-[[1-[(2-biphenyl-4-ylethyl)carbamoyl]-4-(2-fluorophenyl)but-3- yny l]amino]methyl]phosphonic acid (56), an arylacetylene amino phosphonate amide, had IC50's of 33 nM and 6.5 microM for ECE-1 and NEP, respectively. Slight modification of the aryl moiety was found to have dramatic effects on ECE-1/NEP selectivity. The 2-fluoro dipeptide analogue, (S, S)-2-[[5-(2-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (40), showed a 72-fold selectivity for ECE-1 over NEP, while the 3-fluoro dipeptide analogue, (S, S)-2-[[5-(3-fluorophenyl)-2-[(phosphonomethyl)amino]pent-4-ynoyl]+ ++amin o]-4-methylpentanoic acid (22), was equipotent for ECE-1 and NEP. Several of these inhibitors were shown to be potent in blocking ET-1 production in vivo as demonstrated by the big ET-1-induced pressor response in rats. These potent inhibitors are the most selective for ECE-1 reported to date and are envisaged to have a variety of therapeutic applications.     

Synthesis and antitumor activity of novel benzophenone derivatives

Novel benzophenone derivatives were synthesized and screened for cytotoxic and antitumor activity. Friedel-Crafts condensation was employed to construct the benzophenone skeleton. Among the compounds synthesized, morpholino and thiomorpholino benzophenones 3a-d exhibited potent cytotoxic activity against P388 murine leukemia and PC-6 human lung carcinoma cells in vitro, and compounds 3a, 3c, and 3j, when administered intraperitoneally, showed significant antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice.     

Design and synthesis of new potent, silent 5-HT1A antagonists by covalent coupling of aminopropanol derivatives with selective serotonin reuptake inhibitors

Hybrid molecules built up by covalent coupling of aminopropanol derivatives (especially pindolol) with antidepressant drugs like fluoxetine, paroxetine or milnacipran were found to be potent and silent 5-HT1A antagonists (KB < 1 nM for 7c and 9a).     

Preclinical antitumor activity of water-soluble paclitaxel derivatives

PURPOSE: Five water-soluble paclitaxel derivatives were extensively evaluated for their antitumor activities relative to the parent drug. METHODS: Both subcutaneous (s.c.) murine (M109 lung) and human (A2780 ovarian, L2987 lung) tumor models were used for this purpose. RESULTS: Consecutive daily intravenous (i.v.) paclitaxel therapy of mice bearing s.c. M109, beginning on day 4 or 5 posttumor implant and continuing for 5 days, resulted in a range of maximum gross log cell kill (LCK) values (reflective of delays in tumor growth) and maximum relative median survival time (% T/C) values (reflective of increases in lifespan) of 1.0-2.1 and 132-162% (and one outlying result of 235%), respectively. Against the same tumor model, using the same treatment schedule, each of the water-soluble derivatives was active, with maximum LCK of 1.3-2.5 and T/C of 124-254%. These LCK and %T/C values were always within 0.5 LCK and 15%, respectively, of the concomitantly obtained maximum effects of paclitaxel. When tested in several experiments against staged (50-100 mg) s.c. A2780 tumors, using various i.v. treatment schedules, the water-soluble derivatives achieved a maximum LCK of 1.4-3.8. Evaluated in parallel, paclitaxel achieved a maximum LCK of 2.1-4.5 following every other day x 5 i.v. therapy. When paclitaxel was assayed in several experiments using the staged (50-100 mg) s.c. L2987 tumor model, maximum LCK of 0.9->4.1 were produced following every other day x 5 i.v. therapy. Concomitant testing of the water-soluble derivatives, using the same i.v. treatment schedule, resulted in maximum LCK of 0.2->4.1. In each of the tumor models used, the consistently active, and usually the most active, water-soluble derivative was BMS-185660. The levels of activity observed were comparable (within 1 LCK) to those achieved concomitantly using paclitaxel, and its potency was only slightly inferior to the parent drug. CONCLUSIONS: Based on the evaluations performed in three distal site tumor models, we conclude that BMS-185660 is a water-soluble paclitaxel derivative with preclinical antitumor activity comparable to that of the parent drug.     

N alpha-alkylated derivatives of 2-phenylhistamines: synthesis and in vitro activity of potent histamine H1-receptor agonists

New potent N alpha-alkylated histamine H1-receptor agonists have been prepared and functionally evaluated for partial agonist potency and selectivity. N alpha-Methyl-2-(3-trifluoromethylphenyl)histamine contracts ileal segments and aortic rings of guinea-pig with a relative potency of 174% (95% confid. lim. 161-188%) and 217% (164-287%), respectively (histamine: 100%) and is the most potent H1 receptor agonist described so far.     

Mode of action of bullatacin: a potent antitumor and pesticidal annonaceous acetogenin

Bullatacin, a compound isolated from plants of the Annonaceae, and its analogues show in vivo potential as antitumor agents based on their efficacy in normal mice bearing L1210 murine leukemia and athymic mice bearing A2780 conventional ovarian cancer xenografts. These compounds also have interesting potential as insecticides and inhibit respiration in insect-derived Sf9 cells with high potency. Their toxicity in both cases probably arises from their strong inhibition of mitochondrial electron transport with a specific action at complex I.     

Thyroid status and exercise tolerance. Cardiovascular and metabolic considerations

Both hypo- and hyperthyroidism are characterised by exercise intolerance. In hypothyroidism, inadequate cardiovascular support appears to be the principal factor involved. Insufficient skeletal muscle blood flow compromises exercise capacity via reduced oxygen delivery, and endurance through decreased delivery of blood-borne substrates. The latter effect results in increased dependence on intramuscular glycogen. Additionally, decreased mobilisation of free fatty acids from adipose tissue and, consequently, lower plasma free fatty acid levels compound the problem of reduced lipid delivery to active skeletal muscle in the hypothyroid state. In contrast, cardiovascular support is enhanced in hyperthyroidism, implicating other factors in exercise tolerance. Greater reliance on muscle glycogen appears to be the primary reason for decreased endurance. Biochemical changes with hyperthyroidism that would favour enhanced flux through glycolysis may account for this dependence on glycogen. Deviations from normal thyroid function, and the ensuing exercise tolerance, require appropriate medical therapy to attain euthyroid status.     

Design, synthesis, and biological activities of potent and selective somatostatin analogues incorporating novel peptoid residues

We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to the Merck cyclic hexapeptide c[Pro6-Phe7-d-Trp8-Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with arylalkyl peptoid residues. We present a novel approach utilizing beta-methyl chiral substitutions to constrain the peptoid side-chain conformation. Our studies led to molecules which show potent binding and increased selectivity to the hsst2 receptor (weaker binding to the hsst3 and hsst5 receptors compared to L-363, 301). In vivo, these peptoid analogues selectively inhibit the release of growth hormone but have no effect on the inhibition of insulin. The biological assays which include binding to five recombinant human somatostatin receptors carried out in two independent laboratories and in vivo inhibition of growth hormone and insulin provide insight into the relationship between structure and biological activity of somatostatin analogues. Our results have important implications for the study of other peptide hormones and neurotransmitters.     

Synthesis of 6-aziridinylbenzimidazole derivatives and their in vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a-d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremy's salt to give a mixture of three 2-(acetoxymethyl) (8a-c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a-d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a-c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a-d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters 10d and 13e-h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of 10a-d or 11a-d against SNU-16 were superior to those of 13e-h, and were equal to or slightly higher than that of mitomycin C. Compounds 11a-d were slightly more cytotoxic than 10a-d in all cell lines tested.     

New indole derivatives as potent and selective serotonin uptake inhibitors

A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.