An unusual complication of gastric banding: recurrent small bowel obstruction caused by the connecting tube.

Laparoscopic adjustable gastric banding (LAGB) is a widely performed surgical procedure for morbid obesity. The application of this mini-invasive approach has given the benefits of shorter hospital stay, less postoperative pain and quicker functional recovery. LAGB complications are related either to the access-port, such as port-site infection or tubing disconnection, or to the band, such as band slippage, pouch dilatation, or intragastric migration. We report a case of recurrent small bowel obstruction caused by the connecting tube around a jejunal loop, in a woman who had under-gone LAGB 3 years before. The diagnosis was difficult to establish because the clinical history and examination were non-specific. A 3-dimensional CT scan was needed to explain the cause of the recurrent abdominal pain, and the small bowel loop was freed from the connecting tube at laparoscopy.

Synthesis, antitumor cytotoxicity, and DNA-binding of novel N-5,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides.

A series of DNA-binding potential antitumor agents bearing a cationic carboxamide side chain attached in position peri to an electron-withdrawing atom, N-5,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides, has been prepared by reaction of the appropriate 1-chloro-9-oxo-9,10-dihydro-4-acridinecarboxamides with the suitable (omega-aminoalkyl)hydrazine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure-activity relationships are discussed. Two highly DNA-affinic and potent cytotoxic compounds, 4m,o, have been identified as new leads in the antitumor strategies.

N4-(omega-Aminoalkyl)-1-[(omega-aminoalkyl)amino]-4- acridinecarboxamides: novel, potent, cytotoxic, and DNA-binding agents.

A series of DNA-binding potential antitumor agents, (omega-aminoalkyl)-4-acridinecarboxamides, has been prepared either by reduction of the corresponding (omega-aminoalkyl)-9-oxo-9, 10-dihydro-4-acridinecarboxamides with aluminum amalgam or by aminolysis of the corresponding (omega-aminoalkyl)-1-chloro-4-acridinecarboxamides with the suitable amine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780-sensitive, A2780cisR cisplatin-resistant, CH1-sensitive, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. One highly DNA affinic analogue (3a) has been identified with a useful broad spectrum of cytotoxic activity in the 4-7 nM range (mean IC(50) of 6 nM).

The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

2,3-Dihydro-1H,7H-pyrimido[5,6,1-de]acridine-1,3,7-trione derivatives, a class of cytotoxic agents active on multidrug-resistant cell lines: synthesis, biological evaluation, and structure-activity relationships.

A series of DNA-intercalating potential antitumor agents, (amino)alkyl-substituted 2,3-dihydro-1H,7H-pyrimido[5,6, 1-de]acridine-1,3,7-triones, has been prepared by aminolysis of the corresponding 6-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward eight tumor cell lines, including human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR (cisplatin-resistant), CH1, CH1cisR (cisplatin-resistant), and SKOV-3) cells, are described and compared to that of reference drugs. The cytotoxic activity often parallels the observed DNA affinities, for almost all the target compounds. Interesting structure-activity relationships have been found. The octanol/water partition coefficients have also been calculated, but there was no correlation either with cytotoxicity values or with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have been identified with a useful broad spectrum of cytotoxic activity.

Pyrimido[4,5,6-kl]acridines. Synthesis, in vitro cytotoxicity and structure-activity relationships.

In a previous report we described the synthesis and biological properties of a group of pyrimido[4,5,6-kl]acridines 2, related to the pyrazolo[4,5,6-kl]acridines 1, promising antitumor agents possessing a broad spectrum of activity. Since the substitution of the pyrazole ring of the pyrazoloacridine chromophore with a pyrimidinone leads to derivatives that retain in vitro cytotoxic activity, we decided to further investigate the pyrimido[4,5 6-kl]acridines. Modifications at the ring system level, leading to chromophores with different characteristics, changes of substituent groups in position 6, simultaneous alteration of the chromophore and the introduction of a second cationic side chain in position 1 afforded 29 new pyrimido[4,5,6-kl]acridines, which were tested in vitro against the human colon adenocarcinoma HT29 cell line. Interesting structure-activity relationships could be drawn. Some selected derivatives were screened for their cytotoxic activity on the National Cancer Institute cell panel (60 human tumor lines).

1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: synthesis, DNA binding, and biological evaluation.

A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity.

Pyrimido [4,5,6-kl] acridines, a new class of potential anticancer agents. Synthesis and biological evaluation.

A series of 3-(aminoalkyl)-2,7-dihydro-6-nitropyrimido [4,5,6-kl] acridin-2-ones 3, strictly related to the pyrazoloacridines 1, have been synthesized. Thus, the reaction of the suitable 1-(aminoalkyl)amino-9, 10-dihydro-9-imino-4-nitroacridine 2 with ethyl chloroformate afforded the pyrimidoacridines 3a-f. By hydrolysis in hydrobromic acid of the 10-methoxy derivatives 3d-f, the 10-hydroxy derivatives 3g-i were obtained. The pyrimidoacridines 3a-i were tested in vitro for their cytotoxic activity against L1210 murine leukemia and HT29 human colon adenocarcinoma cell lines, showing significant potency of growth inhibition. Different DNA-binding assays as well as attempts to correlate cytotoxicity and DNA affinity have been carried out.

Synthesis and biological evaluation of mono- and bis-[(alkylamino)alkylamino] substituted thienopyridopyridazines, a new class of potential antitumor agents.

A new class of potential antitumor agents, provided with thieno[2',3':5,6]pyrido[2,3-d]pyridazin-9(4H)-one nucleus as chromophore, was synthesized. Thus, the suitable amines were reacted, in different conditions, with 5,8-dichlorothieno[2',3':5,6]pyrido[2,3- d]pyridazin-9(4H)-one (5) to afford the 8-alkylamino derivatives 6a-f, the 5-alkylamino derivatives 7a-f, and the 5,8-bis-alkylamino derivatives 8a,b. Selected compounds were evaluated for cytotoxic potency in vitro against the human colon adenocarcinoma HT 29 cell line and studied in DNA binding assays. The cytotoxic potency versus HT29 was also correlated with binding affinity for calf thymus DNA.

Synthesis of (dialkylamino)alkyl-disubstituted pyrimido[5,6,1- de]acridines, a novel group of anticancer agents active on a multidrug resistant cell line.

A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.

Synthesis of 9,10-anthraquinone monoalkylaminoalkylhydrazones as potential antitumor drugs.

In the constant search for new compounds endowed with antitumor activity we have synthesized a series of anthraquinone hydrazones, which can bee seen either as opened-cycle modified anthrapyrazoles or as chromophore-modified anthracenediones. Seven 9,10-anthraquinone monoalkylaminoalkylhydrazones (3c-i) were synthesized from 10,10-dibromoanthrone (4) and a suitable N-alkylhydrazine. The hydrazones were converted into hydrochlorides and tested for their cytotoxic activity against L1210 murine leukemia cells. Two of them possess marginal activity in vitro.

Synthesis of 7-oxo-7H-benzo[e]perimidine-4-carboxamides as potential antitumor drugs.

A series of 7-oxo-7H-benzo[e]perimidine-4-carboxamides (4a-f) was synthetized from the corresponding acid (3) and the suitable amines by the "mixed anhydride" method. The amide derivatives were tested for antitumor activity against P 388 leukemia "in vivo". Only the N-[2-(diethylamino)ethyl]-7-oxo-7H-benzo[e]perimidine-4-carboxa mid e (4b) shows borderline antineoplastic activity.

Pyrimidoacridine derivatives as potential antitumor agents.

A series of some N-alkylaminoalkyl derivatives of pyrimido[5,6,1-d,e]acridine-1,3,7-trione (3) was synthesized as new potential antitumor drugs, starting from the suitable 9,10-dihydro-9-oxo-4-acridinecarboxamides and using phosgene as cyclizing agent. 1-(9,10-dihydro-9-oxo-4-acridinecarbonyl)-3-alkyl-2-imidazolido nes were also obtained as side products. The final products 3 and some carboxamides were tested "in vitro" against L 1210 leukemia and "in vivo" against P388 leukemia. Of the tested compounds, one is active "in vivo", another shows significant cytotoxic activity "in vitro", but is inactive or toxic "in vivo".

Heterocyclic quinones with potential antitumor activity. 2. Synthesis and antitumor activity of some benzimidazole-4,7-dione derivatives.

A series of benzimidazole-4,7-dione derivatives, bearing substituents at positions 1, 2, 5, and 6 of the benzimidazole ring, has been synthesized and tested for antitumor activity in vivo on P388 leukemia. Some of the synthesized compounds show significant antitumor activity, associated with high toxicity, however. Compounds 7, 18, and 27 show the highest antitumor activity in this series, whereas 17, 19, and 22 are scarcely active. Some hypothetical biological precursors of these quinones are devoid of antitumor activity. Some structure-activity relationships are discussed.

2,2'-Bipyridyl-6-carbothioamide derivatives as potential antitumor agents.

4- and/or 4'-substituted 2,2'-bipyridyl-6-carbothioamides have been synthesized and tested for their activity against P-388 lymphocytic leukemia in mice. Of these, only 4'-nitro-2,2'-bipyridyl-6-carbotioamide (IV c) proved to be active.

(o- and p-Nitrobenzyloxycarbonyl)-5-fluorouracil derivatives as potential conjugated bioreductive alkylating agents.

A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition. Measurement of the surviving fractions of EMT6 tumor cells treated with these agents in culture under conditions of hypoxia and aerobiosis resulted in equal cell kill regardless of the state of oxygenation. One of the synthesized agents, 3-(p-nitrobenzyloxycarbonyl)-5-fluorouracil (4), appeared to be superior to 5-fluorouracil in prolonging the survival time of mice bearing intraperitoneal implants of the P388 leukemia and Sarcoma 180.

2,3-Dimethyl-1,4-naphthoquinone derivatives as bioreductive alkylating agents with cross-linking potential.

Bioreducible 2,3-disubstituted 1,4-naphthoquinones have been synthesized and evaluated for anticancer activity by measuring their capacity to prolong the life span of Sarcoma 180 tumor bearing mice. The leaving group in the 2- and 3-positions of these agents significantly influenced the degree of antineoplastic activity, with the most active agents being the methyl sulfonate (5), the methyl carbamate (9), and the 2-chloroethyl carbamate (10) derivatives; when these quinones were administered daily for 6 consecutive days, they produced maximum T/C X 100 values of 232, 266, and 230, respectively.

Deaza analogues of adenosine as inhibitors of blood platelet aggregation.

A number of deaza analogues of adenosine were prepared and tested as inhibitors of platelet aggregation induced by ADP and collagen to investigate the structure-activity relationships in this class of nucleoside analogues. The results showed that the presence of a 6-amino group and nitrogen atoms at positions 3 and 7 of the purine moiety are required for inhibitory activity.

Adenosine deaminase inhibitors. Synthesis of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

Structural analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), in which the adenine moiety of the molecule was modified, were prepared in order to investigate the structural requirement of EHNA as an inhibitor of adenosine deaminase (ADA). Thus, 1- and 3-deaza-EHNA and their 6-deamino analogues were synthesized and evaluated as inhibitors of ADA from calf intestine. Inhibition studies indicated that isosteric substitution of pyrimidine nitrogens by carbons could be tolerated at the enzymatic binding site. In fact, 3-deaza-EHNA was found to have an inhibitory activity comparable to EHNA itself, and 1-deaza-EHNA, though less potent, is a good inhibitor. The 6-amino group gives an important contribution to the enzymatic binding if the N1 nitrogen is also present, conferring on the compound the characteristic of a semitight inhibitor.