Antitumor activity of triazine mimic antibiotics for DNA-binding implications (impressive activity in vitro against a variety of tumor types in the NCI-60 screen): NSC 710607 to fight HCT-116 human colon carcinoma cell lines in vivo using the hollow fiber assay and xenograft mouse models.

PURPOSE: Successful clinical applications of DNA-directed selective cytotoxic agents disrupt the vital replication/transcription processes and ultimately lead to cancer cell death. This study aimed to examine the growth screen of two lead triazine compounds in a number of cell lines and xenografts and to develop anticancer agents with noncovalent binding affinity bringing fewer side effects. METHODS: The NCI initial hollow fiber test was performed using an established procedure. The cytostatic and cytocidal capacities of the test compounds were assessed by evaluating cytotoxicity by simply performing a standard cellular viability assay. The nude mouse human tumor xenograft system was used as an in vivo model. RESULTS: More sensitive drug with sub-micromolar activity met the interdisciplinary criteria for testing and was referred to evaluations in subcutaneous colorectal carcinoma HCT-116 human tumor xenografted into nude mice. Principal findings of the study: total cytostasis, almost nontoxic schedules, specific working hypotheses, strong rationale for the potential use, and important general implications (relevance to human biology). NSC 710607 displayed in vivo better than Cisplatin and 5-fluorouracil abilities to significantly decrease tumor growth. CONCLUSION: Cell proliferation can be reduced or stopped in vivo in view of the xenograft results. The mimic molecule behaves as DNA-binding antitumor antibiotics with great potential as general anticancer agents and deserves further trials. NSC 710607 represents the result of a design strategy with outstanding potential. This study also identifies the prognostic significance and is likely to translate to other species or systems.

Selective cytostatic and cytotoxic anticancer effects of bisfunctional agents: A strategy for the design of DNA binding agents.

Various agents have been synthesized and proved useful for the National Cancer Institute's anticancer testing as potential new drugs, but most agents suffer side effects from their limited selectivity against cancer cells over healthy ones. Therefore, this paper attempts to describe drugs in terms of the level of tumor cell selectivity which they possess to define the features of molecules that are essential for useful cytotoxicity. Selected cyclic amidinothymine analogues (NSC 697864, NSC 697865, and NSC 697869) have nanomolar inhibitory activities against leukemia cell lines: CCRF-CEM, HL-60(TB), while bisfunctional cancer fighters NSC 702408 and NSC 702409, showing larger numbers of cytostatic and cytotoxic effects, in an extended conformation would probably adopt a similar to NSC 715653 conformation leaving both opposite H-bond donor groups at the same distance to interact with DNA in a similar way. Such specific interactions (cell line selectivity to unique mutated patterns) lower considerably the observed dose-response concentrations. This in vitro selectivity is shown to translate into in vivo efficacy indicated by the inflection in the cumulative testing curve.

4,4'-(1,2,4,5-Tetra-zine-3,6-di-yl)dibenzo-nitrile.

Mol-ecules of the title compound, C(16)H(8)N(6), lie on crystallographic inversion centres. A dihedral angle of 16.1 (1)° is formed between the central tetra-zine ring and the plane of each cyano-phenyl group. The mol-ecules form stacks along [100] with a perpendicular inter-planar separation of 3.25 (1) Å. C-H⋯N inter-actions are formed between mol-ecules in neighbouring stacks.

The usefulness of cyclic diamidines with different core-substituents as antitumor agents.

A series of related polycationic compounds has been screened for potential antitumor activity by the NCI's in vitro testing (one dose primary anticancer assay and the NCI-60 full panel screening). The GI50 values of triazines 3 and 4 are on average 1.9 microM and 2.4 microM, respectively. Furan 8 deserves mention too (1.9 microM). The biological test results showed that carbazole 10 possessed cytotoxic activity in the nanomolar range, much better than the other compounds tested, only against several cancer cell lines: CCRF-CEM, HL-60(TB), MOLT-4, NCI-H522, COLO 205, SF-268, but the average GI50 value was higher (15 microM). The activity appears closely dependent on the core-shape and length of the bisimidazoline molecules (important for both high cytotoxicity and DNA binding). The mechanism of DNA minor-groove binding of diamidines 1-12, based on the anticancer parameters, is highly probable.

Supramolecular motifs in 1-(2-cyanoethyl)thymine and 1-(3-cyanopropyl)thymine.

In both 1-(2-cyanoethyl)thymine [systematic name: 3-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)propanenitrile], C(8)H(9)N(3)O(2), (I), and 1-(3-cyanopropyl)thymine [systematic name: 4-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)butanenitrile], C(9)H(11)N(3)O(2), (II), the core of the supramolecular structure is formed by centrosymmetric dimers generated by N-H...O hydrogen bonds. Further weak hydrogen bonds of C-H...O and C-H...N types generate molecular tapes and sheets that resemble those in uracil and its methyl derivatives. The steric hindrance that arises from the cyanoalkyl substituents perturbs the conformations of the tapes and sheets.

(Z)-N-[2-(Dimethyl-ammonio)eth-yl]thio-acetamide chloride.

The thio-amide and quaternary amine parts of the title compound, C(6)H(15)N(2)S(+)·Cl(-), are mutually almost perpendicular, the dihedral angle being 80.6 (7)°. The thio-amide group is planar and adopts a Z conformation, whereas the amine end of the cation is in an extended conformation. In the supra-molecular structure, mol-ecules are linked into centrosymmetric dimers by two hydrogen bonds: N-H(amine)⋯Cl and N-H(thio-amide)⋯Cl.

Molecular packing in (5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetamide.

In the title compound, C7H9N3O3, the primary packing motif, viz. an infinite tape, is formed via intermolecular hydrogen bonds of different strengths. In the formation of the tapes, only inversion centres are used; the other symmetry elements of P2(1)/c connect the tapes into a three-dimensional structure through only weak hydrogen bonds.