Synthesis and structure-activity relationships of benzo[b]thienylallylamine antimycotics

Benzo[b]thiophene analogues of the allylamine antimycotic terbinafine (2) bearing the side chain at various positions and optionally substituted by halogen have been prepared and their antifungal activity studied. Derivatives bearing the side chain at positions 3, 4, or 7 are bioequivalents of 2. Compounds containing the allylamine side chain at position 7, with a further substituent at position 3, showed significantly enhanced activity against Candida albicans, an effect which appears to be specifically linked only to this particular substitution pattern. 3-Chloro-7-benzo[b]thienyl derivative 7m was found to be the most potent allylamine antimycotic identified so far. In general, substituted benzo[b]thiophenes can be used not only as potential equivalents of naphthalene in bioactive compounds but also as a tool to selectively modify biological activities.     

2-(aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines, a new class of anticancer agents.

2-(Aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines were prepared from substituted anilines via the 1-chloro-4-nitroacridones followed by condensation with [(alkylamino)alkyl]hydrazines. Impressive activity was demonstrated for the 9-hydroxy, 9-alkoxy, and 9-acyloxy analogs in vitro on a L1210 leukemia line and in vivo against the P388 leukemia. Advanced studies led to the selection of 3bbb for clinical trial.     

Synthesis and antiprotozoal activity of [1,3]oxazino[4,5,6-de]quinolines

The synthesis of 1,3-oxazino-anellated 4-amino-5-hydroxy-quinolines has been investigated. Cyclisation to 2,3-dihydro[1,3]oxazino[4,5,6-de]quinoline-2-ones/-2-thiones (2/3) was achieved by reaction with 1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole. Cyclocondensation with aldehydes yielded 2,3-dihydro[1,3]oxazino[4,5,6-de]quinoline-derivatives (5). All new tricyclic compounds exhibited weak antiprotozoal activity against Plasmodium falciparum.     

2-l-Rhamnopyranosyl[1,2,4]triazolo[1,5-a]pyridine. 4' and 3' Oxidation products. Synthesis and structure-activity relationships

A series of 2-alpha-L-rhamnopyranosylnitro[1,2,4]triazolo[1,5-a] pyridine C-nucleosides was synthesized from the condensation oa thioiminoether with nitro-2-pyridylhydrazines. Catalytic reduction afforded the corresponding amino derivative. A 1',2' unsaturated C-nucleoside was also obtained by two different routes. Selective oxidation gave the 3'- and 4'-ketonucleosides. The cytotoxic properties of the nucleosides, as well as their effect on viral transformation and replication, were described. The nitro derivatives inhibit viral replication, but at toxic doses; the introduction of a keto function leads to a product which inhibits the replication of murine leukemia virus (MuLV) at noncytotoxic concentrations. The amino derivatives have no significant antiviral effect.     

Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists

A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.     

Resistance-modifying agents. 11.(1) Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to alpha1-acid glycoprotein

The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of (3)H-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'-dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.     

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.     

Dipyrazolo[5,4-b:3',4'-d]pyridines. Synthesis, inhibition of benzodiazepine receptor binding and structure-activity relationships

Some 2,6,8-trisubstituted dipyrazolo[5,4-b:3',4'-d]pyridin-3-ones related to the CGS series were synthesized and tested for their ability to displace [3H]flunitrazepam binding from bovine brain membranes. However the affinity for the benzodiazepine receptor of the tested compounds was lower than that of the CGS series, although it was comparable to that of chlordiazepoxide. It follows that some structure-activity relationships on the tested compounds can be drawn.     

Synthesis and structure-activity relationships of deltorphin analogues.

In order to study the structure-activity relationships of natural opioid deltorphins (H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2 and H-Tyr-D-Ala-Phe-Asp [or Glu]-Val-Val-Gly-NH2), 15 analogues were synthesized by the solution method. Their activities were determined in binding studies based on displacement of mu- and delta-receptor selective radiolabels from rat brain membranes and in two bioassays, using guinea pig ileum and mouse vas deferens. The obtained data indicate that the high delta-selectivity of deltorphins can be due to the constitution/conformation of the C-terminal part and, at least in part, to preselection by charge.     

Synthesis and Chemical Properties of 1-Aryl-substituted Pyrimido[5,4-b]indoles

Pharmaceutical Chemistry Journal -     

New Approach to the Synthesis of Benzo[G]Pyrimido[4,5-B]Indoles

Pharmaceutical Chemistry Journal -     

Synthesis, cytotoxicity and structure-activity relationship study of terpyridines

For the development of novel antitumor agents, we designed and synthesized terpyridines, and their biological activities were evaluated. Although most of the newly prepared terpyridines showed strong cytotoxicity against several human cancer cell lines, [2,2';6',2"]-terpyridine displayed the most significant cytotoxicity.     

Synthesis, structure-activity relationships, and RARgamma-ligand interactions of nitrogen heteroarotinoids.

Three heteroarotinoids containing a nitrogen atom in the first ring and a C-O linking group between the two aryl rings were synthesized and evaluated for RAR and RXR retinoid receptor transactivation, tumor cell growth inhibition, and transglutaminase (TGase) induction. Ethyl 4-(N,4,4-trimethyl-1,2,3,4-tetrahydroquinolinyl)benzoate (1) contained an N-CH(3) group and activated all retinoid receptors except for RARgamma. Inceasing the hydrophobicity around the rings with analogues ethyl 4-(N,4,4,7-tetramethyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (2) [7-methyl group added] and ethyl 4-(4,4-dimethyl-N-isopropyl-1,2,3, 4-tetrahydroquinolin-6-oyloxy)benzoate (3) [NCH(CH(3))(2) group at C-4] increased the potency and specificity for RARalpha, RARbeta, and RXRalpha, compared to 1, but had little effect on RXRbeta and RXRgamma activation. Although 1 and 3 were unable to activate RARgamma, 2 did activate this receptor with efficacy and high potency equal to that of 9-cis-retinoic acid (9-c-RA). All three heteroarotinoids exhibited 5-8-fold greater specificities for RARbeta over RARalpha. In addition, esters 1-3 inhibited the growth of two cell lines each derived from cervix, vulvar, ovarian, and head/neck tumors with similar efficiencies to that of 9-c-RA through a mechanism independent of apoptosis. The vulvar cell lines were the most sensitive, and the ovarian lines were the least sensitive. Ester 2 was similar to 1 and 3 except that 2 was a much more potent growth inhibitor of the two vulvar cell lines, which is consistent with strong RARgamma activation by 2 (but not by 1 and 3) and the high levels of RARgamma expression in skin. All three heteroarotinoids induced production of TGase, a marker of retinoid activity in human erythroleukemic cells. Esters 2 and 3 were the more potent TGase activators than 1, in agreement with the stronger activation of the RAR receptors by 2 and 3. The biological activities of these agents, and the RARgamma potency of 2 in particular, demonstrate the promise of these compounds as pharmaceutics for cancer and skin disorders.     

Tricyclic heteroaromatic systems. [1]benzopyranopyrrol-4-ones and [1]benzopyrano-1,2,3-triazol-4-ones as benzodiazepine receptor ligands. Synthesis and structure-activity relationships

The synthesis, ability to displace [3H]flunitrazepam binding from bovine brain membranes, and GABA ratio of some [1]benzopyranopyrroles 1a-i and [1]benzopyrano-1,2,3-triazoles 2a,b are reported. The GABA ratios of some previously synthesized pyrazoloquinolines A and [1]benzopyranopyrazoles C are also presented in order to draw some structure-activity relationships among our benzodiazepine receptor ligands. 1,3-Diarylpyrrole derivatives 1a-h show similar affinity and efficacy to that of diazepam, while the 1-aryltriazoles 2a,b have no receptor affinity. Comparison of the latter results with those on previously reported compounds suggests that there are several hydrophobic regions on the benzodiazepine recognition site whose occupation gives rise to different affinity and efficacy.     

Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents

The growth-inhibitory activities of an extensive series of quaternized quino[4,3,2- kl]acridinium salts against tumor cell lines in vitro have been measured and their biological properties interpreted in the light of differential binding to different DNA isoforms. Selectivity for quadruplex DNA binding and stabilization by compounds were explored through an array of methods: UV absorption and fluorescence emission spectroscopy, surface plasmon resonance, and competition dialysis. Quadruplex DNA interaction was further characterized through FRET and DNA polymerase arrest assays. Telomerase inhibition, inferred from the TRAP assay, is attributed to quadruplex stabilization, supported by the strong correlation (R(2) = 0.81) across the series between quadruplex DNA binding affinity and TRAP inhibition potency. Growth inhibition potency in the NCI60 human tumor cell line panel is more marked in compounds with greater DNA duplex binding affinity (R(2) = 0.82). Quantification of relative quadruplex and duplex binding affinity constants puts some of these ligands among the most selective quadruplex DNA interactive agents reported to date.     

Synthesis and structure-activity relationships of pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists

A series of 21 1,3-dialkylpyrazolo[4,3-d]pyrimidin-7-ones substituted in the 5-position with various phenyl substituents has been synthesized and found to have affinity for the adenosine A1 receptor. The potency pattern due to substituents of the phenyl ring was found to parallel that found in a previously reported 1,3-dialkyl-8-phenylxanthine series. A quantitative structure-activity relationship was developed between these two series that correctly predicted the potencies of six additional 5-substituted pyrazolo[4,3-d]pyrimidines that were synthesized during the course of the analysis. With use of the correlation as a guide, one additional 5-phenylpyrazolo[4,3-d]pyrimidine containing a 4-[[(dimethylamino)ethyl]amino]sulfonyl substituent to improve aqueous solubility was prepared. On the basis of the high correlation between adenosine binding affinities of analogously substituted xanthines and pyrazolo-[4,3-d]pyrimidines and the close superposition of the heterocyclic rings and substituents that is apparent from molecular models of these two series, it is hypothesized they fit the receptor in an analogous fashion.     

Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents

The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]acridinecarboxamides 8 prompted us to the synthesis of two new series of bis acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the bis derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and (iv) in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. 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. We could identify six very potent cytotoxic compounds for further in vitro studies: a cytotoxic screening against six human cancer cell lines and the National Cancer Institute (NCI) screening on 60 human tumor cell lines. Finally, compound 6a was selected for evaluation in a NCI in vivo hollow fiber assay.     

Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: structure-activity relationships for cytotoxicity and antitumor activity

A large number of aziridinyl quinones represented by series 1-9 were studied with respect to their DT-diaphorase substrate activity, DNA reductive alkylation, cytostatic/cytotoxic activity, and in vivo activity. As a result, generalizations have been made with respect with respect to the following: DT-diaphorase substrate design, DT-diaphorase-cytotoxicity quantitative structure-activity relationship (QSAR), and DNA reductive alkylating agent design. A saturating relationship exists between the substrate specificity for human recombinant DT-diaphorase and the cytotoxicity in the human H460 non-small-cell lung cancer cell line. The interpretation of this relationship is that reductive activation is no longer rate-limiting for substrates with high DT-diaphorase substrate specificities. High DT-diaphorase substrate specificity is not desirable in the indole and cylopent[b]indole systems because of the result is the loss of cancer selectivity along with increased toxicity. We conclude that aziridinyl quinones of this type should possess a substrate specificity (V(max)/K(M)) < 10 x 10(-4) s(-1) for DT-diaphorase in order not to be too toxic or nonselective. While some DNA alkylation was required for cytostatic and cytotoxic activity by series 1-9, too much alkylation results in loss of cancer selectivity as well as increased in vivo toxicity. Indeed, the most lethal compounds are the indole systems with a leaving group in the 3alpha-position (like the antitumor agent EO9). We conclude that relatively poor DNA alkylating agents (according to our assay) show the lowest toxicity with the highest antitumor activity.