Synthesis and Antitumor Activity of s-Tetrazine Derivatives.
Hu WX, Rao GW, Sun YQ: Synthesis and antitumor activity of s-tetrazine derivatives. Bioorg. Med. Chem. Lett. 2004, 14:1177.
Synthesis and Antitumor Activity of s‐Tetrazine Derivatives.
In this study, following treatment with thistetrazine derivative, we found that ZGDHu-1 inhibited theproliferative effect and enhanced apoptosis in PANC-1 cells, andblocked its cell cycle at G2/M phase. Furthermore, themitochondrial pathway and activation of caspase-3 are important inZGDHu-1-induced apoptosis, and the nuclear factor inhibitor IκB wasalso involved in this process. CyclinB1, cdc2 and Chk1 are G2/Mregulatory molecules, whose expression levels were alteredfollowing the treatment of ZGDHu-1.
The imidazotetrazine bicycle is a prodrug of alkyldiazonium ions which are liberated by pH-dependent hydrolysis. Careful control of these reactive intermediates, in particular the suppression of competing side reactions, such as hydrolysis, elimination or re-arrangement,- is essential in the design of effective new agents., Furthermore, of the methyl groups transferred from TMZ to DNA, only a small fraction becomes the therapeutically-beneficial O6-MeG lesion: we sought to achieve therapeutic benefit though generation of N7-G-adducts, the major products of reaction of TMZ with DNA, thereby making more efficient use of the imidazotetrazine prodrug. We have designed novel series of mono-(2a-i) and bi-functional (3a–f) imidazotetrazines in which a 3-(2-anilinoethyl) group was substituted for the 3-methyl group of TMZ. The new compounds are efficient precursors of aziridinium ions, 4, . This strategy provides for effective control of the reactivity of incipient diazonium ions using a neighboring group participation mechanism not available to TMZ. Moreover, aziridinium ions are reactive intermediates of proven clinical utility, being closely related to those generated by nitrogen mustard drugs, and are established as working through N7-guanine adducts. An additional feature of the drug design is the aniline para-substituent “X” of derivatives 2 and 3 that can be optimized to fine-tune pharmacological activity. This group affects the electron density at the aniline nitrogen by resonance or inductive effects and thereby controls the basicity and nucleophilicity of this site: i.e. the propensity either to protonate or to form an aziridinium ion. In addition, the bi-functional molecules would be expected to generate DNA cross-links, that would not be processed by MMR or MGMT and so avert those constraints on activity; previous studies have demonstrated that polar and bulky GO6 adducts cannot be processed by MGMT.
Synthesis and Antitumor Activity of s-Tetrazine Derivatives
3,6-bis(1H-1,2,3,4-tetrazol-5-yl-amino)-1,2,4,5-tetrazine (BTATz) was synthesized by the condensation of triaminoguanidinium nitrate with 2,4-pentanedione, followed by oxidation and substitution reaction. The product was characterized by elemental analysis, IR, NMR spectrometry and DSC analysis. Instead of nitrogen dioxide/N-methylpyrrolidone, acetic acid/sodium nitrite was used as the oxidizer during the oxidation. Thus, the cost was reduced and the process was simplified. The theoretical properties of BTATz were estimated by a B3LYP method based on a 6-31G(d,p) basis set, and the stable geometric configuration and bond order were obtained. The vibrational frequencies, IR spectrum and thermodynamic properties under different temperatures were obtained from vibrational analysis and the relationship between temperature and thermodynamics properties was deduced. Pyrolysis mechanism of BTATz was discussedand the transition state and activation energy of ring opening reaction of the tetrazole were deduced.
A concise (9 step) and effective (19% overall yield) total synthesis of ningalin D (1a) is disclosed and is based on a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole Diels–Alder strategy to assemble a fully substituted pyrrole core central to its structure. Additional highlights of the synthesis include a double Dieckmann condensation to introduce the C and D aryl rings enlisting substituents judiciously placed on the dienophile and intrinsic to the widely used tetrazine 2, a highly effective Suzuki coupling of the resulting C and D phenol triflates for introduction of the sterically demanding F and G aryl rings, and an unusually effective formal oxidative decarboxylation reaction cascade initiated by a Curtius rearrangement to directly provide the biphenylene quinone methide found imbedded in the structure of ningalin D. The cytotoxic and multidrug resistance (MDR) reversal activity of ningalin D, its derivatives, and the key synthetic intermediates are detailed.
Synthesis and antitumor activity of s-tetrazine ..
niger, of the prepared series.Quinazolinone, Antibacterial activity, Antifungal activityINTRODUCTION: The quinazolinone skeleton is a frequently encountered heterocycle in medicinal chemistry literature with applications including analgesic-anti-inflammatory 1, antibacterial 2, antimalarial 3, CNS depressant- anticonvulsant 4, antihistaminic 5, antiviral 6, antitumor 7 and antitubercular 8 activities.The present work is an effort towards the development and identification of new molecules for antibacterial and anti-fungal activity.On this basis, we synthesized some 3-(4-substituted-phenyl)-2-thioxo-2, 3-dihydroquinazolin-4(1H)-one, 3-(4-substituted-phenyl)-2-(methylthio)quinazolin-4(3H)-one and 3-(4-substituted-phenyl)-2-hydrazinyl quinazolin-4(3H)-one the title compounds, we aimed to synthesize these compounds by a novel innovative route 9 (Figure 1, Reaction Scheme).
First isolated in 1997 by Fenical and Kang, the ningalins constitute a family of structurally interesting and biologically active marine natural products. By far, the most complex of these is ningalin D (1a) incorporating a biphenylene quinone methide superimposed on a now oxidized pentasubstituted pyrrole core that characterizes this class of natural products (). To our knowledge, the only closely related natural product disclosed to date is purpurone (1b), an inhibitor of ATP-citrate lyase whose name reflects the purple color of the natural products and the sponges from which both 1a and 1b were isolated (Didemnum sp. and Iotrochota sp., respectively). In the course of developing total syntheses of the simpler members of the ningalin family, we disclosed several derivatives that possess potent P-gp inhibitory activity, effective multidrug resistance (MDR) reversal properties in cellular functional assays,– and efficacious (potentiation/resensitization) in vivo antitumor activity against sensitive and resistant tumors upon coadministration with antitumor therapeutics (vinblastine, taxol) in xenograph animal models. Although such derivatives lack intrinsic cytotoxic activity themselves, they resensitize MDR tumors and hypersensitize sensitive tumors to conventional therapeutics through inhibition of the overexpressed or constituitive drug effux pump P-gp.–
Synthesis and in vitro antitumor activity of 4 ..
Synthesis and antitumor activity of ..
Synthesis, antitumor activity and SAR study of novel [1,2,4]triazino[4,5-a]benzimidazole derivatives
Synthesis and Antitumor Activity of 3- ..
and antitumor activity of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives.
Synthesis, X-ray crystallographic analysis, ..
Synthesis and antitumor activity of N,N'-Bis(substitutedphenyl)-3, 6-dialkyl-1, 4-dihydro-s- tetrazine-1 ..
X-ray crystallographic analysis and antitumor activity ..
-Tetrazine based molecules were prepared for visible-light-driven organic transformations. The 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) derivative shows visible light absorption and reversible one-electron reduction behavior. In the presence of pytz and aerial oxygen, aldehyde reacts with -phenylenediamine or -aminothiophenol under visible light irradiation at ambient temperature to produce corresponding 2-substituted benzimidazoles and benzothiazoles, respectively. Pytz catalyst demonstrates excellent catalytic activity for alkyl, aryl, organo-metallic substituted aldehydes and reducing sugar. The reaction yield is high for both the electron-donating and electron withdrawing substituents in aromatic aldehydes. The use of a metal-free catalyst and visible light energy, along with the mild reaction conditions, makes this reaction an environmentally benign and energy-saving chemical process.
Dimere Aldehyd-hydrazone - Kauffmann - Wiley Online …
As a consequence of these biological observations with the simpler ningalin derivatives and because of the intrinsically interesting structure of ningalin D, we have pursued and herein detail the first total synthesis of ningalin D in studies that complement the only other reported efforts in the area, a biomimetic total synthesis of purpurone disclosed by Steglich. Key elements of the concise and nonobvious approach include an inverse electron demand heterocyclic azadiene Diels–Alder reaction (1,2,4,5-tetrazine → 1,2-diazine) followed by a reductive ring contraction of the resultant 1,2-diazine affording the fully substituted pyrrole core central to the structure of 1 (). A double Dieckmann cyclization enlisting substituents judiciously placed on the dienophile (–CH2CO2Me) and intrinsic to the widely used tetrazine 2 (–CO2Me) was used to close the C and D aryl rings, the sterically demanding F and G aryl rings were introduced enlisting a highly effective Suzuki coupling onto the corresponding C and D ring phenol triflates, and an unusually effective formal oxidative decarboxylation reaction cascade initiated by a Curtius rearrangement was discovered to directly provide the biphenylene quinone methide of ningalin D.
An improved synthesis of 3,6‐diamino‐1,2,4,5‐tetrazine. …
A series of 3-aryl[1,2,3,5]tetrazino[5,4-a]benzimidazole-4(3H)-thione derivatives have been synthesized. The compounds were synthesized in excellent yields (65-75%) and the structures were established on the basis of corresponding IR, 1H NMR, Mass and elemental analysis data. The purity has been ascertained on the basis of chromatographic resolution using CH2Cl2 as eluent.
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