Biomedical subjects

G J Atwell

Publications and source records attributed to G J Atwell.

At least 37 records · Page 2Linked to original sources

PubMed1991

Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids.

Analogues of 9-oxo-9H-xanthene-4-acetic acid (XAA) bearing small, lipophilic 5-substituents are among the most dose-potent compounds yet reported with the capability of causing hemorrhagic necrosis of implanted colon 38 tumors in mice. To further extend structure-activity relationships among this class of compound, a series of XAA derivatives bearing two small lipophilic groups at various positions have been prepared and evaluated. The 5,6-disubstituted compounds in particular show consistently high levels of both dose potency and activity, suggesting this is the optimal configuration among substituted 9-oxo-9H-xanthene-4-acetic acids. The 5,6- dimethyl and 5-methyl-6-methoxy are the most effective analogues, showing in vivo colon 38 activity comparable to that of FAA at 10-15-fold lower doses and superior activity to FAA at the respective optimal doses, and the former has been selected for detailed evaluation.

Animals↗

PubMed1991

Potential antitumor agents. 62. Structure-activity relationships for tricyclic compounds related to the colon tumor active drug 9-oxo-9H-xanthene-4-acetic acid.

A series of tricyclic analogues of 9-oxo-9H-xanthene-4-acetic acid have been prepared and evaluated for their ability to cause hemorrhagic necrosis in subcutaneously implanted colon 38 tumors in mice, in an effort to extend the structure-activity relationships for this series. As was found previously with analogues of flavone-8-acetic acid (FAA) (Atwell et al. Anti-Cancer Drug Des. 1989, 4, 161), all electronic modifications of the XAA nucleus led to severe decreases or complete abolition of activity, suggesting narrow structure-activity relationships. Dipole moments for many of the compounds were computed, and the degree to which the molecular dipole moment lay out of the plane of the aromatic part of these molecules was found to be determined largely by the contributions from the acetic acid moiety relative to that from the tricyclic ring system. There did not appear to be any general relationship between the magnitude of the dipole moment and activity. However, for compounds containing the 9-carbonyl functionality, the orientation of the dipole vector may be of significance. In all compounds possessing an ether group peri to the acetic acid side chain, there was a close approach (ca. 2.4 A) between this and the side chain OH.

Animals↗

PubMed1991

Potential antitumor agents. 63. Structure-activity relationships for side-chain analogues of the colon 38 active agent 9-oxo-9H-xanthene-4-acetic acid.

A series of 16 analogues of the solid tumor active compound 9-oxo-9H-xanthene-4-acetic acid (XAA), with variations in the acetic acid side chain, have been prepared and evaluated for their ability to cause early haemorrhagic necrosis of colon 38 tumors in mice. The results extend the previous SAR for this class and confirm the necessity for a carboxylic acid group in a fixed disposition with respect to the xanthenone chromophore. None of the compounds showed superior potency to XAA itself, with virtually all alterations in the nature of the anionic center or its geometry with respect to the chromophore greatly reducing or abolishing activity. However, alpha-methylation of the side chain was permissible, and the two enantiomers of 5-methyl-alpha-methyl-XAA were separated and tested. Both were active, but the S-(+) enantiomer was much more dose-potent than the R-(-) enantiomer, in both the in vivo tumor necrosis assay and an in vitro assay measuring the stimulation of nitric oxide production by macrophages. This suggests that the enantiomers have different intrinsic activities, rather than differing in their vivo metabolism.

Animals↗

PubMed1990

Structure-activity relationships for the mutagenic activity of tricyclic intercalating agents in Salmonella typhimurium.

A total of 25 different tricyclic DNA-intercalating chromophores bearing a common -CONH(CH2)2N(CH3)2 solubilizing sidechain have been compared with the 'classical' frameshift mutagen 9-aminoacridine for their ability to induce revertants in Salmonella typhimurium strain TA1537 (sensitive to frameshift mutation by acridine mutagens). The compounds showed varying levels of activity in this strain. For the fused linear and fused angular tricyclics, activity varied from zero to similar levels to 9-aminoacridine, but with no discernable relationship between activity and either structure or the measured physico-chemical properties. However, the '2-1' tricyclic compounds had essentially no mutagenic activity. Since several of these compounds have high in vivo antitumor activity, this is useful knowledge.

Frameshift Mutation↗

PubMed1990

Hypoxia-selective antitumor agents. 4. Relationships between structure, physicochemical properties, and hypoxia-selective cytotoxicity for nitracrine analogues with varying side chains: the "iminoacridan hypothesis".

The nitroacridine derivative nitracrine is a potent hypoxia-selective cytotoxin for mammalian cells in culture. In an attempt to modulate the degree of hypoxia selectivity among this class of compounds, we have studied a series of side-chain analogues of nitracrine. Both the electronic and steric properties of the side chain are shown to be important in determining the hypoxia selectivity of the compounds, by controlling the degree of aminoacridine/iminoacridan tautomerism. Studies with the repair-defective Chinese hamster cell line UV4 indicate that the cytotoxicity of all the compounds is due to nitro group reduction and subsequent macromolecular adduct formation. However, compounds such as the 9-amino derivative, which exist totally as the aminoacridine tautomer, form much less lethal lesions than the 9-alkylamino derivatives, which exist to varying degrees in the iminoacridan conformation. For the whole set of compounds, the degree of hypoxia-selective cytotoxicity correlates well with the proportion of iminoacridan tautomer present.

Aminoacridines↗

PubMed1990

Potential antitumor agents. 60. Relationships between structure and in vivo colon 38 activity for 5-substituted 9-oxoxanthene-4-acetic acids.

9-Oxoxanthene-4-acetic acids are a class of antitumor agents effective against the mouse colon adenocarcinoma 38 in vivo. Within this class, 5-substituents on the xanthenone are known to enhance potency. To extend structure-activity relationships for the class, a series of derivatives bearing a wide variety of substituents at the 5-position have been prepared and evaluated. The results suggest that activity correlates better with the lipophilic properties of substituents rather than with their electronic properties. Generally, lipophilic substituents result in more active compounds, but there may be a size limitation on such substituents. The 5-methyl derivative is the most dose-potent of the analogues studied.

Acetates↗

PubMed1989

Potential antitumor agents. 57. 2-Phenylquinoline-8-carboxamides as "minimal" DNA-intercalating antitumor agents with in vivo solid tumor activity.

A series of phenyl-substituted derivatives of the "minimal" DNA-intercalating agent N-[2-(dimethylamino)-ethyl]-2-phenylquinoline-8-carboxamide (1) have been synthesized and evaluated for in vivo antitumor activity, in a continuing search for active compounds of this class with the lowest possible DNA association constants. Substitution on the 2'-position of the phenyl ring gave compounds of lower DNA binding ability that did not intercalate DNA, indicating that it is necessary for the phenyl ring to be essentially coplanar with the quinoline for intercalative binding. An extensive series of 4'-substituted derivatives was evaluated, but there was no overall relationship between biological activity and substituent lipophilic or electronic properties. However, several compounds showed good solid tumor activity, with the 4'-aza derivative 18 being clearly superior to the parent compound, effecting about 50% cures in both leukemia and solid tumor models.

Amides↗

PubMed1989

Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo.

In a search for compounds related to flavoneacetic acid with activity against solid tumors, a series of methyl-, methoxy-, chloro-, nitro-, and hydroxy-substituted xanthenone-4-acetic acids have been synthesized and evaluated against subcutaneously implanted colon adenocarcinoma 38 in vivo, using a short-term histology assay as a primary screening system. A major goal of this work was to identify compounds with similar profiles of activity to that of flavoneacetic acid but of higher potency. The level of activity of the compounds appeared to depend more on the nature of the substituent than its positioning, in the order Cl greater than Me, OMe greater than NO2, OH. However, the potency of the compounds was related much more to the position rather than the nature of the substitution, with 5-substituted compounds being clearly the most dose potent. 5-Methylxanthenone-4-acetic acid has a similar level of activity to that of flavoneacetic acid in the test systems employed but is more than 7-fold as dose potent.

Acetates↗

PubMed1989

Synthesis and anti-tumour activity of topologically-related analogues of flavoneacetic acid.

A number of structural analogues of the solid tumour active drug flavoneacetic acid have been prepared and evaluated for in vivo activity against colon 38 adenocarcinoma, in order to extend the limited structure-activity relationships available for compounds with this type of activity. Apart from the fused ring analogue xanthenone-4-acetic acid, structural and electronic modifications of the nucleus led to inactive compounds, suggesting the existence of quite narrow structure-activity relationships.

Adenocarcinoma↗

PubMed1988

The relationship between lipophilic-hydrophilic balance, uptake and anti-bacteriophage lambda activity of experimental anti-tumour bisquaternary salts.

The uptake by Escherichia coli of a series of bisquaternary experimental anti-tumour agents (quinolinium 4-[p-9(-pyridylamino)phenylcarbamoyl]-aniline-bisalkyl dibromides) has been measured both by association of radiolabelled compounds and their inhibition of the vegetative replication of bacteriophage lambda (after heat inactivation of the phage repressor) as a measure of biologically effective intracellular drug concentration. Uptake of these compounds was correlated with biological effect, and was a function of both incubation temperature and the lipophilic-hydrophilic balance of the compound. At 30 degrees C uptake was drug concentration-dependent and was not readily reversible. No saturation of uptake was apparent over the concentration range tested. Preliminary experiments indicated that time-dependent drug uptake was also related to growth inhibition in cultured L1210 murine leukaemia cells. These results are consistent with the hypothesis that uptake occurs by diffusion across the plasma membrane followed by strong binding to cell constituents such as DNA. The approximate range of uptake of the most active compounds, using an external drug concentration of 1 microM, are 100 and 2400 molecules/s respectively for bacteria and murine leukemia cells. For bacteria, the uptake of approx. 2 X 10(5) molecules of drug/cell inhibits the yield of phage lambda by 90%.

Animals↗

PubMed1988

Potential antitumor agents. 54. Chromophore requirements for in vivo antitumor activity among the general class of linear tricyclic carboxamides.

Structure-antitumor activity relationships are reported for a number of different examples (acridine, phenazine, anthracene, acridone, xanthenone, thioxanthenone, anthraquinone, pyridoquinazoline, dibenzodioxin, thianthrene, phenothiazine, phenoxazine, dibenzofuran, carbazole, and pyridoindole) of the general class of N-[2-(dimethylamino)ethyl] linear tricyclic carboxamides. Only the compounds containing coplanar chromophores intercalated DNA. There is an absolute requirement for an oxygen or aromatic nitrogen (possibly as hydrogen-bond acceptors) peri to the carboxamide, together with a planar ring geometry for biological activity. In addition to further delineating the nature of the pharmacophore for this class of compounds, the work has also identified dibenzo[1,4]dioxin as a novel DNA-intercalating chromophore with in vivo antitumor activity.

Aminacrine↗

PubMed1988

Potential antitumor agents. 55. 6-Phenylphenanthridine-4-carboxamides: a new class of DNA-intercalating antitumor agents.

Derivatives of the DNA-intercalating agent N-[2-(dimethylamino)ethyl]phenanthridine-4-carboxamide have been prepared and shown to have moderate in vivo antitumor activity against both the P388 leukemia and Lewis lung carcinoma. This demonstrates that the effective pharmacophore in the broad class of tricyclic carboxamides is not limited to linear tricyclic chromophores. Both 7 and the 6-phenyl derivative 10 have identical DNA binding properties, suggesting that the phenyl ring of 10 is not involved in the DNA intercalation site. A series of phenyl-substituted derivatives of 10 was evaluated. Aza substituents led to compounds with the highest in vivo cytotoxicity and in vivo P388 activity, but the in vivo solid tumor activity of the substituted 6-phenylphenanthridine-4-carboxamides was in general low.

Animals↗

PubMed1988

Potential antitumor agents. 56. "Minimal" DNA-intercalating ligands as antitumor drugs: phenylquinoline-8-carboxamides.

A series of isomeric phenylquinoline-8-carboxamides have been synthesized and evaluated as antitumor agents. This configuration is close to the minimum chromophore required for intercalative binding, since the binding mode of the compounds is dependent on the presence and position of the phenyl ring. If the ring is appended at the 4- or 5-position, it cannot lie within the DNA-intercalation site, and the compounds do not intercalate as shown by both unwinding and helix extension assays. In contrast, the 2-, 3-, and 6-phenyl isomers (where the phenyl ring lies coplanar with the quinoline and in the intercalation site) bind by intercalation. Only those isomers that intercalate show in vivo antitumor activity, with the 2-phenyl derivative in particular possessing broad-spectrum activity in both leukemia and solid-tumor assays.

Animals↗

PubMed1987

Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity.

Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.

Amsacrine↗

PubMed1987

Potential antitumor agents. 49. 5-substituted derivatives of N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide with in vivo solid-tumor activity.

Derivatives of N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide bearing a wide variety of different groups at the 5-position (and for comparative purposes at the 7-position) have been prepared, and their physicochemical properties and biological activities have been determined. Although both 5- and 7-substituted compounds bind equally well to DNA by intercalation, only the 5-substituted compounds have in vivo antitumor activity. All the 5-substituted compounds showed in vivo antileukemic activity, but only those bearing electron-withdrawing substituents sufficiently powerful to ensure the acridine chromophore was uncharged at physiological pH showed activity in vivo against the Lewis lung solid tumor. The weakly basic derivatives do not show greater intrinsic cytotoxicity or selectivity toward solid tumor cells, and their broader spectrum of in vivo antitumor activity is attributed to the fact that they exist predominantly as monocations, which can distribute more efficiently.

Aminoacridines↗

PubMed1987

Potential antitumor agents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

The synthesis, physicochemical properties, and antitumor activity of a series of N-[2-(dialkylamino)alkyl]-acridine-4-carboxamides are reported. The compounds bind to DNA by intercalation, but exist under physiological conditions as monocations due to the weakly basic acridine chromophore (pKa = 3.5-4.5). The acridine-4-carboxamides show very broad structure-activity relationships (SAR) for antileukemic activity, with substituents at nearly all acridine positions proving acceptable. The compounds also show remarkable activity against the Lewis lung solid tumor in vivo, with several analogues capable of effecting 100% cures of the advanced disease. The broad SAR and high solid-tumor activity of the 9-acridine-4-carboxamides imply they should be considered as a completely new class of antitumor agent.

Aminoacridines↗

PubMed1987

Relationships between DNA-binding kinetics and biological activity for the 9-aminoacridine-4-carboxamide class of antitumor agents.

The kinetics of dissociation of calf thymus DNA complexes of the new intercalating antitumor drug N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (5) and selected derivatives have been investigated by using the surfactant-sequestration method. The derivatives studied include those where the position (14 and 15) and nature of attachment (20 and 21) of the cationic side chain is modified, those where the distance (16-19) and composition (22-24) of the cationic group are varied, and those in which the chromophore is further substituted (25-31). While all of the compounds dissociate by a mechanism that involves at least three intermediate bound forms, derivatives bearing a 4-CONH(CH2)2NR1R2 side chain (where R1 and R2 are groups that permit the nitrogen to be protonated at neutral pH) have access to an additional binding mode of greater kinetic stability. A positive correlation is found between in vivo antitumor activity, selectivity of binding to GC-rich DNAs, and the presence of this fourth, long-lived transient species. We have interpreted our kinetic findings in terms of a molecular model for acridinecarboxamide-DNA complexes that accounts for the appearance of the fourth component. The acridine chromophore is postulated to intercalate from the narrow groove, its major axis lying at an angle to the major axis of the base pairs so that the CH atoms of positions 5 and 6 protrude into the groove. An important feature of the model is a bifurcated hydrogen bond between the O2 oxygen atom of a cytosine base adjacent to the binding site and the NH atoms of the carboxamide and protonated terminal amino functions of the drug molecule. Since the structural features required to form this bonding interaction are necessary, although not sufficient, conditions for in vivo antitumor activity, it is suggested that the model may describe the essential characteristics of the biologically active form of the bound drug. These findings further attest to the value of investigating the kinetics of DNA-drug interaction in studies of the mode of action of antitumor intercalating agents.

Amides↗

PubMed1987

Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia.

Study of a series of aniline-substituted 9-anilinoacridines related to the antileukemic drug amsacrine showed that a 1'-carbamate group provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar, with 3-halo-5-methyl and 3-halo-5-methoxy compounds proving the most active. This substitution pattern also provided the highest DNA binding. Such compounds (particularly the 3-chloro-5-methyl and 3-chloro-5-methoxy) have in vivo activity against wild-type P388 and Lewis lung comparable to that of the best amsacrine analogues previously developed (greater than 50% cures), as well as P388/ADR activity. This work essentially completes the development of the amsacrine series of antitumor agents.

Amsacrine↗