• Archives of Pharmacal Research
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• v.19 no.6
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• pp.535-542
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• 1996

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1, 2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, with .omicron.-chloronitrotoluene as the starting material. Nitration of 3 produced a mixtue of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36 : 52. 4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and 11) were synthesized by 1, 4-addition of 7 with cyclic secondary amines. From above-mentioned 5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of 15 produced quinone (16), whereas iminoquinone derivatives (17a and 17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and 11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them, 8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and 17b) revealed very weak cytotoxicity.

• Proceedings of the Korean Vacuum Society Conference
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• 2016.02a
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• pp.432.2-432.2
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• 2016

A new A-D-A type (Acceptor-Donor-Acceptor) conjugated based on pyridine-borane complex (Donor), non-boron fluorine (Donor) and 2,5-bis(alkyl)-3,6-di(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione (DPP) (Acceptor) were designed and synthesized via Pd-catalyzed Suzuki cross-coupling reaction. The synthesized boron based complex exhibited high electron affinity, which indicates deep HOMO energy levels and good visible absorption led to their use as donors in BHJ (bulk heterojunction) solar cells. Inverted devices were fabricated, reaching open-circuit voltage as high as 0.91eV. To probe structure-property relationship and search for design principle, we have synthesized pyridine-boron based electron donating small molecules. In this study, we report a new synthetic approach, molecular structure, charge carrier mobility and morphology of blended film and their correlation with the photovoltaic J-V characteristics in details.

• Archives of Pharmacal Research
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• v.24 no.5
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• pp.455-465
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• 2001

The highly potent cytotoxic DNA-DNA cross-linker consists of two cyclopropa[c]pyrrolo[3,4-3]indol-4(5H)-ones insoles [(+)-CPI-I] joined by a bisamido pyrrole (abbreviated to "Pyrrole"). The Pyrrole is a synthetic analog of Bizelesin, which is currently in phase II clinical trials due to its excellent in vivo antitumor activity. The Pyrrole has 10 times more potent cytotoxicity than Bizelesin and mostly form DNA-DNA interstrand cross-links through the N3 of adenines spaced 7 bp apart. The Pyrrole requires a centrally positioned GC base pair for high cross-linking reactivity (i.e., $5^1$-T$AT_2$A*-$3^1$), while Bizelesin prefers purely AT-rich sequences (i.e., $5^1$-T$AT_4$A*-$3^1$, where /(equation omitted) represents the cross-strand adenine alkylation and A* represents an adenine alkylation) (Park et al., 1996). In this study, the high-field $^1$H-NMR and rMD studies are conducted on the 1 1-mer DNA duplex adduct of the Pyrrole where the 5′(equation omitted)TAGTTA*-3′sequence is cross-linked by the drug. A severe structural perturbation is observed in the intervening sequences of cross-linking site, while a normal B-DNA structure is maintained in the region next to the drug-modified adenines. Based upon these observations, we propose that the interplay between the bisamido pyrrole unit of the drug and central C/C base pair (hydrogen-bonding interactions) is involved in the process of cross-linking reaction, and sequence specificity is the outcome of those interactions. This study suggests a mechanism for the sequence specific cross-linking reaction of the Pyrrole, and provides a further insight to develop new DNA sequence selective and distortive cross-linking agents.

• Journal of Microbiology and Biotechnology
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• v.20 no.2
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• pp.433-437
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• 2010

In the course of screening for novel modulators of cell cycle progression and apoptosis as anticancer drug candidates, we generated an analog of sangivamycin, MCS-C2, which was elucidated as 4-amino-6-bromo-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. In the present study, we evaluated the molecular mechanisms of MCSC2-induced cell cycle arrest and apoptosis in A549 human lung cancer cells. To investigate the effects of MCS-C2 on cell cycle progression in A549 cells, we measured the DNA content of A549 cells treated with $5\;{\mu}M$ MCS-C2 using flow cytometry. The analysis revealed an appreciable $G_2$ phase arrest in treated cells. This event was associated with significant upregulation of p53 and $p21^{Cip1}$. In addition, the TUNEL assay was used to examine apoptotic induction in treated cells, and the effects of MCS-C2 on the expression of apoptosis-associated proteins were examined by Western blot. Apoptotic induction in MCS-C2-treated A549 cells was associated with cytochrome c release from mitochondria, which in turn resulted in the activation of caspase-9 and -3 and the cleavage of poly(ADP-ribose) polymerase (PARP). Based on these results, we conclude that MCS-C2 is a candidate therapeutic agent for the treatment of human lung cancer via upregulation and activation of p53.