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G J Atwell

Publications and source records attributed to G J Atwell.

At least 55 records · Page 3Linked to original sources
PubMed1987

'Minimal' DNA-intercalating agents as anti-tumour drugs: 2-styrylquinoline analogues of amsacrine.

A series of analogues of amsacrine have been prepared by replacing the acridine with a variety of other chromophores, in a search for 'minimal' DNA-intercalating anti-tumour agents which might show superior distributive properties as a consequence of lower levels of binding to cellular macromolecules. 2-Styrylquinoline derivatives did show in vivo anti-leukaemic activity, but none of the compounds was superior to amsacrine itself.

Amsacrine↗
PubMed1986

Potential antitumor agents. 45. Synthesis, DNA-binding interaction, and biological activity of triacridine derivatives.

A series of amide-linked triacridines of varying interchromophore separation were synthesized as potential DNA trisintercalating agents. The corresponding diamide diacridines (lacking the central chromophore) were also prepared, and the DNA-binding and biological activities of both series of compounds were evaluated. Although one of the triacridines shows evidence of a trisintercalative binding mode, most of the triacridines (and all the diacridines) bound by bisintercalation. The diacridines showed great cytotoxicity and higher DNA association constants than the corresponding 9-[[3-(dimethylamino)propyl]amino]acridine monomer, but addition of a third chromophore did not provide corresponding increases in either DNA affinity, inhibition of RNA synthesis, or cytotoxicity. Some members of both series show minimal in vivo antileukemic activity. The results suggest that further development of trimeric molecules as potential antitumor agents should focus on smaller chromophores with lower capacity for nonspecific binding and/or the employment of rigid linker chains to provide true molecular "staples" for DNA.

Acridines↗
PubMed1986

Potential antitumor agents. 46. Structure-activity relationships for acridine monosubstituted derivatives of the antitumor agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide.

A series of monosubstituted derivatives of the new antitumor agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide has been prepared, bearing methyl, methoxy, and chloro groups at available acridine positions. The physicochemical properties and antitumor activity of these compounds varied more with the position than with the nature of the substituent groups. The highest levels of both in vitro and in vivo antileukemic activity were shown by 5-substituted derivatives, while 7- and 8-substituted derivatives possessed the highest selectivity toward the HCT-8 human colon carcinoma line compared to the L1210 mouse leukemia line in vitro.

Aminoacridines↗
PubMed1986

Potential antitumor agents. 47. 3'-Methylamino analogues of amsacrine with in vivo solid tumor activity.

Replacement of the 3'-methoxy group of the clinical antileukemic agent amsacrine with a 3'-methylamino group provides a compound (3) with a broader spectrum of action, including in vivo activity against experimental solid tumors. The synthesis, physicochemical properties, and biological activity of a series of acridine-substituted analogues of 3 are described. The compounds show higher levels of DNA binding, water solubility, and in vivo solid tumor activity (lewis lung carcinoma) than their amsacrine counterparts. However, the structure-activity relationships for acridine substitution are different, with 3,5-disubstituted 3'-methylamino compounds showing the highest activity (compared to 4,5-disubstituted amsacrine analogues).

Acridines↗
PubMed1985

Interaction of paired homologous series of diacridines and triacridines with deoxyribonucleic acid.

Viscometric measurements using covalently closed circular DNA and sonicated rod-like DNA fragments were performed to investigate unwinding and extension of the DNA helix associated with binding of paired homologous series of diacridines and triacridines. The maximum interchromophore distance for members of the diacridine series spans from 15.1 to 27.5 A, permitting the largest of these ligands to cover up to 4 or 5 base-pairs, allowing for helical twist and local unwinding in a bisintercalated complex lacking severe bending or kinking of the DNA backbone. Helix unwinding angles and increments in DNA contour length are characteristic of bifunctional reaction for all the diacridines studied, the DNA lattice appearing to saturate with one ligand molecule bound per 4 base-pairs. The triacridines, whose maximum end-to-end interchromophore distances are the same as those of their paired diacridines, have maximum central-to-terminal interchromophore distances covering the range 7.5-13.8 A and thus have the potential to form trisintercalated complexes with one or two base-pairs sandwiched between each chromophore. However, helix extension and unwinding parameters for the triacridines are similar to those of the diacridines, and we find no evidence of a transition from bifunctional to trifunctional reaction as the homologous series is ascended. In general, the binding site size appears to be 5 base-pairs for the triacridines. The stereochemical requirements for trisintercalation of triacridines are discussed with reference to the present findings and to the work of others.

Acridines↗
PubMed1985

Potential antitumor agents. 44. Synthesis and antitumor activity of new classes of diacridines: importance of linker chain rigidity for DNA binding kinetics and biological activity.

Four classes of diacridines, joined at the 9-position by linker chains of varying length, rigidity, and polarity, were evaluated for DNA-binding properties and antitumor activity. Diacridines linked by flexible chains of varying polarity show relatively fast chromophore exchange kinetics among DNA binding sites but slower dissociation rates, suggesting the potential for considerable "creeping" of the drug along the helix, and are inactive in vivo. The exchange kinetics can be slowed dramatically by inclusion of positive charges in the side chain, but the resulting polycationic drugs are inactive in vivo, possibly due to poor distribution. Diacridines linked by a rigid, polar but neutral dicarbamoylpyrazole chain retain slow exchange kinetics, have a greatly reduced potential "creep rate", and possess good in vitro potency and significant in vivo antileukemic activity.

Acridines↗
PubMed1984

Potential antitumor agents. 40. Orally active 4,5-disubstituted derivatives of amsacrine.

The DNA-intercalating agent amsacrine is an effective drug for the treatment of human leukemias and lymphomas but has minimal solid tumor activity. As a first step in identifying analogues with a wider spectrum of activity, a comparison was made of the in vivo antileukemic (P-388) activity of amsacrine analogues given by oral (po) and intraperitoneal (ip) routes. A series of 4-substituted and 4,5-disubstituted derivatives all showed high activity when administered ip against ip-implanted P-388, but activity varied widely when the compounds were given orally. 4-Methoxy and 4-carbamoyl derivatives proved essentially inactive, whereas 4-methyl and 4-methylcarbamoyl derivatives retained activity. Exceptional oral activity was shown by the 4-methyl-5-methylcarbamoyl derivative, making this amsacrine derivative worthy of further testing.

Administration, Oral↗
PubMed1984

Potential antitumor agents. 41. Analogues of amsacrine with electron-donor substituents in the anilino ring.

The preparation and antitumor activity of a series of 3'-alkylamino and 3'-dialkylamino analogues of amsacrine are reported. The results support previous work suggesting that the presence of electron-donating groups in the 3'-position of the anilino ring substantially enhance the antitumor activity of amsacrine analogues, possibly by the provision of high levels of electron density at the 6'-position. The alkylamino derivatives generally possess tighter DNA binding, higher levels of in vitro and in vivo antileukemic activity, and greater aqueous solubility than the corresponding amsacrine analogues.

Aminoacridines↗
PubMed1984

Potential antitumor agents. 42. Structure-activity relationships for acridine-substituted dimethyl phosphoramidate derivatives of 9-anilinoacridine.

Replacement of the 1'-methanesulfonamide group of the 9-anilinoacridine class of antitumor agents with the 1'-(dimethyl phosphoramidate) group provides compounds that are generally more lipophilic and bind more tightly to DNA. On the average, the dimethyl phosphoramidates are twice as dose potent as the corresponding methanesulfonamide (AMSA) compounds against P388 leukemia in vivo, but also show about twice the acute toxicity and no resultant improvement in tumor cell selectivity (ILSmax values) is seen. A pairwise comparison of a range of acridine-substituted compounds shows that structure-activity relationships within each series are similar and dominated by the acridine substitution pattern.

Aminoacridines↗
PubMed1984

Potential antitumor agents. 43. Synthesis and biological activity of dibasic 9-aminoacridine-4-carboxamides, a new class of antitumor agent.

The synthesis and biological activities of representatives of a new class of antitumor agent, the N-[2-(dialkylamino)ethyl ]-9-aminoacridine-4-carboxamides, are reported. Members of this class are stable and very water soluble with high levels of in vitro and in vivo antitumor activity. The compounds bind tightly to double-stranded DNA by intercalation, but the requirements for antitumor activity are more restrictive. They depend critically on the separation distance, positioning, and pKa values of the two cationic centers. For in vivo activity, significant bulk tolerance exists for lipophilic but not hydrophilic groups about the C-9 acridine position and for both lipophilic and hydrophilic groups on the side-chain cationic moiety. Significant attenuation of the pKa of the side-chain cationic center abolishes activity, as does alteration of either the disposition or separation distance of the side-chain charge with respect to the chromophore.

Adenocarcinoma↗
PubMed1984

Synthesis, antitumor activity, and DNA binding properties of a new derivative of amsacrine, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide.

The 4-(N-methylcarboxamido)-5-methyl derivative of amsacrine (NSC 249 992) has been synthesized as part of a program aimed at optimizing solid tumor activity in this series. Physicochemical studies of this analogue (N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide; NSC 343 499) indicate a slightly increased lipophilicity (estimated log p = 1.10), a decreased acridine base strength (pKa 6.40), and a 16-fold-higher association constant for double-stranded calf thymus DNA (Ka 2.1 X 10(6) M-1 at 0.01 ionic strength). Like amsacrine, the drug binds to DNA by intercalation. Inhibition of cell growth has been monitored by continuous drug exposure assays with a variety of rodent and human cell lines. The concentration for 50% inhibition varied from 6.7 nM (T-47D, a human breast carcinoma line) to 800 nM (P388/ADR, a murine cell line resistant to Adriamycin). N-5-Dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide was cytotoxic at growth-inhibitory concentrations and also induced cell cycle arrest in the G2 phase. It was active against P388 leukemia following administration by p.o., i.v., or i.p. routes, and it was superior to amsacrine, daunorubicin, and Adriamycin. It was curative towards i.v.-injected Lewis lung tumor in a proportion of animals when treatment was started on Day 1 or Day 5 after tumor inoculation. It also produced highly significant life extensions against advanced tumors (treatment starting Day 9 after i.v. inoculation or on Day 8 after s.c. inoculation) and was comparable to cyclophosphamide in its effectiveness. It is a candidate drug for clinical trial.

Aminoacridines↗
PubMed1983

Potential antitumor agents. 38. 3-substituted 5-carboxamido derivatives of amsacrine.

The synthesis and biological evaluation of a series of 3-substituted 5-carboxamido derivatives of amsacrine (m-AMSA) are described. This series was developed as the result of previous quantitative structure-activity relationship (QSAR) studies of the antitumor activity of 9-anilinoacridine derivatives. In agreement with these studies, this class of compounds, possessing a variety of small nonpolar groups at the 3-position, together with very hydrophilic carboxamido groups at the 5-position, have high in vivo activity against animal leukemia models.

Aminoacridines↗
PubMed1983

Potential antitumor agents. 39. Anilino ring geometry of amsacrine and derivatives: relationship to DNA binding and antitumor activity.

The clinical antileukemic drug amsacrine and analogues are thought to exert their biological activity by binding tightly but reversibly to DNA, with the acridine chromophore intercalated and the anilino group making additional binding contact in the minor groove of the double helix. In this binding model the steric environment around the 3'- and 5'-positions of the anilino ring is crucial. Two 3',5'-disubstituted analogues of amsacrine have been prepared, and their conformation, DNA binding properties, and antitumor activity were determined and compared with corresponding unsubstituted and 3'-substituted compounds. Addition of 3'- and 3',5'-substituents have little effect on minimum-energy conformations of the anilino side chain but have significant effects on DNA binding and biological activity. Monosubstitution lowers binding constants several-fold, but intercalative binding with extensive drug-base pair overlap is retained. Disubstitution lowers binding further, and although the binding is still intercalative as assessed by unwinding angles, it appears to occur with little drug-base pair overlap, as determined by high-field NMR studies of DNA imino proton shifts. These changes in DNA binding are accompanied by an abrupt change in biological activity, with the 3',5'-disubstituted analogues proving inactive and nontoxic even though other physicochemical properties, such as lipophilicity and stability, remain within acceptable limits. This study provides further evidence that the binding of drugs to DNA has a critical influence on their biological activity.

Aminoacridines↗
PubMed1982

Potential antitumor agents. 36. Quantitative relationships between experimental antitumor activity, toxicity, and structure for the general class of 9-anilinoacridine antitumor agents.

Quantitative relationships (QSAR) have been derived between antileukemic (L1210) activity and agent physicochemical properties for 509 tumor-active members of the general class of 9-anilinoacridines. One member of this class is the clinical agent m-AMSA (NSC 249992). Agent hydrophobicity proved a significant but not a dominant influence on in vivo potency. The electronic properties of substituent groups proved important, but the most significant effects on drug potency were shown by the steric influence of groups placed at various positions on the 9-anilinoacridine skeleton. The results are entirely consistent with the physiologically important step in the action of these compounds being their binding to double-stranded DNA by intercalation of the acridine chromophore between the base pairs and positioning of the anilino group in the minor groove, as previously suggested. An equation was also derived for the acute toxicities of 643 derivatives of 9-anilinoacridine. This equation took a somewhat similar form to the one modeling antileukemia potency, emphasizing the usual fairly close relationship between potency and acute toxicity for antitumor agents in general. This study demonstrated the power of QSAR techniques to structure very large amounts of biological data and to allow the extraction of useful information from them bearing on the possible site of action of the compounds concerned.

Aminoacridines↗
PubMed1981

Potential antitumor agents. 34. Quantitative relationships between DNA binding and molecular structure for 9-anilinoacridines substituted in the anilino ring.

In an investigation of the structure-activity relationships in the 4'-(9-acridinylamino)methanesulfonanilide (AMSA) tumor inhibitory analogues, the DNA-binding properties of a series of simple 9-anilinoacridines were examined. Positional numbering as in the AMSA series has been employed. DNA binding was determined by drug competition with the fluorochrome ethidium for available sites. The decrease in fluorescence of a DNA-ethidium complex by the addition of drug is due to both drug displacement of bound ethidium and quenching of the fluorescence of bound ethidium by bound drug; measurement of both factors allows drug-DNA association constants (K) to be determined. DNA binding is augmented by 1' or 2' electron donor substituents, and significant correlation equations have been derived with Hammett's sigma p or sigma m constants. Group molar refractivity (MR) for 1'-substituents is an additional significant regression equation term for binding, while the values for 2' and 3' groups play no significant role. Most 3'-substituents decrease binding, presumably as a result of steric inhibition of entry of the acridine nucleus into intercalation sites. A 3'-NHSO2CH3 and 3'-NHCOCH3 substituent confer selectivity of binding to poly[d(G-C)] and poly[d(A-T)], respectively. It is suggested that a combination of H-bond formation and stereochemical features, coupled with steric hindrance, provides the selectivity observed. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the noncoplanar 9-anilino ring resides in the DNA minor groove.

Acridines↗
PubMed1981

Potential antitumor agents. 35. Quantitative relationships between antitumor (L1210) potency and DNA binding for 4'-(9-acridinylamino)methanesulfon-m-anisidide analogues.

Factors influencing dose potency of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) analogues in L1210 assays have been investigated by multiple regression analysis. The dependent variable was D40, the dose to provide 40% life extension in L1210 tests. Independent variables examined were chromatographic Rm values, as a measure of agent lipophilic-hydrophilic balance; Rm2; log K, where K is the agent-DNA association constant for poly[d(A-T)]; log T1/2, the half-life for congener thiolytic cleavage; and agent pKa values. A regression equation containing terms in Rm2 and log K was derived with the latter term accepting the greater proportion of the biological variance. DNA binding, of acridine substituted m-AMSA variants, is the most important factor influencing dose potency. Modeling of log K for 3-substituted derivatives provided an equation in substituent R constants and molar refractivities (MR).

Aminoacridines↗
PubMed1979

Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles.

Quantitative relationships between physicochemical drug properties and antileukemic (L1210) efficacy have been examined for a series of bisquaternary ammonium heterocycles employing multiple variable regression analysis. Three measures of biologic response were examined: ILSmax, the percentage increase in mean life span of leukemic animals at the LD10 dose; D40, the drug dose necessary to provide 40% increase in life span; and CI (=LD 10/D40), the chemotherapeutic index. A cross correlation matrix between these three measures and the LD10 values demonstrates ILSmax and CI to be independent of toxicity. D40 is highly inversely correlated with LD10 and positively correlated with ILSmax, suggesting that this parameter measures a composite of both drug selectivity and toxicity. Superior regression equations resulted at all stages employing ILSmax as a measure of antitumor selectivity. Acceptable equations modeling LD10 could not be obtained. There was a parabolic relationship between agent lipophilic-hydrophilic balance, measured as chromatographic Rm values, and ILSmax. To reduce residual variance in the L1210 screening data, not accepted by this parabolic equation, measures of agent-DNA interaction were investigated as possible indices of site fit. Relative levels of drug-DNA interaction were obtained by spectrofluorimetric quantitation of drug displacement of DNA-bound ethidium. Addition to regression equations of agent C50 values for calf thymus DNA, those micromolar drug concentrations necessary to displace 50% of the ethidium bound to that DNA, provided a significant reduction in the screening data variance. C50 values for drug interactions with poly[d(A-T)] and poly[d(G-C)] were also investigated as possible indicators of drug selectivity towards different DNA sites. Marked differences were observed in the C50 values for the two synthetic nucleic acids, with those for calf thymus DNA and poly[d(G-C)] proving highly covariant. A regression equation containing a positive term in C50[poly[d(G-C)]] and a negative term in C50-[poly[d(A-T)]] provided the greatest acceptance of the variation in the biologic data. The term in C50[poly[d(A-T)]] is the single most important equation term, alone accounting for 35% of the variance in the data. This best equation provides both an adequate summary of the L1210 screening data for the 174 active compounds considered and a physical explanation for the antitumor selectivity for these agents. The major factor influencing antitumor selectivity in these drugs is their ability to distinguish alternating adenine-thymine sequences in DNA.

Animals↗