Quinoxaline-annelated Z-shaped quadruple-bridged orthocyclophanes: synthesis and crystal structures

A three-step synthesis of nineteen Z-shaped quadruple-bridged [6,6] and [6,4]orthocyclophanes comprising two quinoxaline-based sidewalls are described. The synthesis began from the bis-Diels−Alder adducts B1-B3 followed by ruthenium-promoted oxidation of dichloroetheno-bridges in the adducts to generate a bis-α-diketones, which were then condensed with various arene-1,2-diamines (9a-g) to construct sidewalls (phane parts) of Z-shaped quadruple-bridged orthocyclophanes D1-3, D2g, and D3g. Single-crystal structures of six orthocyclophanes (D1a, D2a, D2f, D3f, D2g-α, and D3g-α) were obtained and revealed that the C_Ar−H?π and π?π stacking interactions between N-containing arene rings are the major driving force for molecular assembly and crystal packing, in addition to the interactions involving the polar OCH₃ groups and the solvate molecules.     

Naphthyridines. Part 3: First example of the polyfunctionally substituted 1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system

Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-[1,5-a]pyridines 2. Chlorination of 2 using POCl₃/DMF (Vilsmeier reagent) led to the isolation of 7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivative 4, which reacted with the stabilized ylid 5 to afford 6-ethoxycarbonylvinyl-1,2,4-triazolo[1,5-a]-pyridines 6. Azidation of 6 yielded the corresponding azido compound 7, (Scheme 2). Reduction of 7 with Na₂S₂O₄ gave the corresponding 7-amino compound 8, which cyclized in boiling DMF to give the novel 1,2,4-triazolo[1,5-g][1,6]naphthyridines 9. On the other hand, reacting 7 with one equivalent of PPh₃ (aza-Wittig reaction) in CH₂Cl₂ gave 7-imino-phosphorane derivative 10, and subsequent cyclization in boiling DMF afforded the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 11 (Scheme 3). However, treatment of 10 with phenyl isothiocyanate in 1,2-dichlorobenzene at reflux temperature gave the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 14 (Scheme 4). Refluxing 6 with excess of a primary amines 15a,b in absolute. EtOH yielded the corresponding 7-alkyl-amino-1,2,4-triazolo[1,5-a]pyridines 16a,b. These obtained amines 16a,b underwent intramolecular heterocyclization in boiling DMF to give the novel 9-alkyl-1,2,4-triazolo[1,5-g][1,6]-naphthyridines 17a,b, in excellent yields (Scheme 5).     

Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Substituted lithiumtrimethylsiloxysilanides LiSiRR′(OSiMe3) - Investigations of their synthesis, stability and reactivity

The reactions of the trimethylsiloxychlorosilanes (Me₃SiO)RR′SiCl (1a-h: R′ = Ph, 1a: R = H, 1b: R = Me, 1c: R = Et, 1d: R = ⁱPr, 1e: R = ^tBu, 1f: R = Ph, 1g: R = 2,4,6-Me₃C₆H₂ (Mes), 1h: R = 2,4,6-(Me₂CH)₃C₆H₂ (Tip); 1i: R = R′ = Mes) with lithium metal in tetrahydrofuran (THF) at −78 °C and in a mixture of THF/diethyl ether/n-pentane in a volume ratio 4:1:1 at −110 °C lead to mixtures of numerous compounds. Dependent on the substituents silyllithium derivatives (Me₃SiO)RR′SiLi (2b-i), Me₃SiO(RR′Si)₂Li (3a-g), Me₃SiRR′SiLi (4a-h), (LiO)RR′SiLi (12e, 12g-i), trisiloxanes (Me₃SiO)₂SiRR′ (5a-i) and trimethylsiloxydisilanes (6f^∗, 6h^∗, 6i^∗) are formed. All silyllithium compounds were trapped with Me₃SiCl or HMe₂SiCl resulting in the following products: (Me₃SiO)RR′SiSiMe₂R″ (6b-i: R″ = Me, 7c-i: R″ = H), Me₃SiO(RR′Si)₂SiMe₂R″ (8a-g: R″ = Me, 9a-g: R″ = H), Me₃SiRR′SiSiMe₂R″ (10a-h: R″ = Me, 11a-h: R″ = H) and (HMe₂SiO)RR′SiSiMe₂H (13e, 13g-i). The stability of trimethylsiloxysilyllithiums 2 depends on the substituents and on the temperature. (Me₃SiO)Mes₂SiLi (2i) is the most stable compound due to the high steric shielding of the silicon centre. The trimethylsiloxysilyllithiums 2a-g undergo partially self-condensation to afford the corresponding trimethylsiloxydisilanyllithiums Me₃SiO(RR′Si)₂Li (3a-g). (Me₃)Si-O bond cleavage was observed for 2e and 2g-i. The relatively stable trimethylsiloxysilyllithiums 2f, 2g and 2i react with n-butyllithium under nucleophilic butylation to give the n-butyl-substituted silyllithiums ⁿBuRR′SiLi (15g, 15f, 15i), which were trapped with Me₃SiCl. By reaction of 2g and 2i with 2,3-dimethylbuta-1,3-diene the corresponding 1,1-diarylsilacyclopentenes 17g and 17i are obtained.X-ray studies of 17g revealed a folded silacyclopentene ring with the silicon atom located 0.5 Å above the mean plane formed by the four carbon ring atoms.     

A one-pot, two step synthesis of 2,2-disubstituted 1-nitroalkenes

The reactions of ketones 1a-o, nitromethane 2, and a stoichiometric amount of piperidine 3a or ethylenediamine 3b in the presence of mercaptan 6a in THF or CH₃CN solution give high yields of β-nitrosulfides 7a-o. The latter can be oxidized by 8a (m-CPBA or m-CPBA/AcOH) at 0°C, 8b (H₂O₂/AcOH), or 8c (H₂O₂) at room temperature, thus generating β-nitroalkylsulfoxides 9a-o, which then undergo elimination to produce medium to high yields of 2,2-disubstituted-1-nitroalkenes 5a-o, when refluxed in a solution of ClCH₂CH₂Cl (1,2-dichloroethane). After preparation from 1a-o, 2, 3, and 6a, 7a-o were oxidized with 8a, 8b, or 8c in a mixture of CH₃CN and ClCH₂CH₂Cl to generate β-nitrosulfoxides 9a-o, which then underwent elimination under refluxing under one-pot conditions. Compounds 14 and 15g were also prepared using 13, 2, 3b, and 6, in a similar manner.     

Nucleophilic fluorination of amino alcohols and diols using Deoxofluor

Various fluorinated chiral compounds were synthesized using bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) as a nucleophilic fluorinating reagent. Reactions of Deoxofluor (1) with amino alcohols (2a-d) and diols (2e-g) in methylene chloride at room temperature led to the formation of the corresponding fluoro derivatives (3a-g) in good yields.     

Chiral binuclear copper(II) catalyzed nitroaldol reaction: scope and mechanism

Chiral binuclear copper(II) Schiff base complexes 4a-g have been prepared from aldehydes 1a,b, (S)-amino alcohols 2a-f, and Cu(OAc)₂·1H₂O in high yield. Their catalysis is studied for the addition of nitroalkanes to aldehydes at ambient conditions with 76:24 er.     

Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P₂S₅ (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P₂S₅ gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol %) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P₂S₅ (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

New synthesis of 3-arylpyrrolines

We present an easy and straightforward synthesis of 3-arylpyrrolines 4a-g by repeated treatment of 4-aryl-1,2,5,6-tetrahydropyridines 2a-g with m-chloroperoxybenzoic acid (MCPBA) and boron trifluoride etherate (BF₃-OEt₂). The transformation proceeds via epoxidation, ring contraction, Baeyer-Villiger oxidation and elimination reaction and affords 3-arylpyrrolines 4a-g with 61-70% yield. This facile strategy was also used to synthesize racemic baclofen (6).     

Ring-opening metathesis polymerization (ROMP) of N-cycloalkyl-7-oxanorbornene dicarboximides by well-defined ruthenium initiators

Ring-opening metathesis polymerization (ROMP) of exo-N-(1-adamantyl)-7-oxanorbornene-5,6-dicarboximide (AdONDI) (3a), exo-N-cyclohexyl-7-oxanorbornene-5,6-dicarboximide (ChONDI) (3b) and exo-N-phenyl-7-oxanorbornene-5,6-dicarboximide (PhONDI) (3c) using well-defined alkylidene ruthenium catalysts (PCy₃)₂(CI)₂RuCHPh (I) and (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) (PCy₃)CI₂RuCHPh (II) was studied. The catalysts I and II gave polymers with around 70% and 50% trans vinylene content, respectively. The homopolymer of 3a had a T_g of 198 °C, while poly-3b showed a T_g of 122 °C. Copolymers of 3a, 3b and 3c with norbornene (NB) showed significant T_g increases over poly-NB.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

A new approach to 2,2-disubstituted 1-(methylsulfanyl)vinyl phosphonates via an intermediate thiocarbonyl ylide

The reaction of methyl (diethylphosphoryl)dithioformate (6) with diaryldiazomethanes 7a-d in THF at −60 °C to room temperature followed by desulfurization is shown to be a convenient method for the preparation of 2,2-disubstituted 1-(methylsulfanyl)vinyl phosphonates 8a-d. The analogous reactions with 2-diazoacenaphthen-1-one (7f) or 2-diazocamphor (7g) in refluxing THF yield selectively the corresponding (Z)- and (E)-vinyl phosphonates 8f and 8g, respectively. These products can be easily oxidized to the vinylsulfoxides 13 and vinylsulfones 14. On the other hand, methyl (diethylphosphoryl)dithioformate (6) and 2-diazo-1,2-diphenylethanone (7e) in boiling THF react to give the 1,3-oxathiole 12. All these reactions occur via an intermediate thiocarbonyl ylide 11 followed by 1,3-dipolar electrocyclization and sulfur extrusion or 1,5-dipolar electrocyclization.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Syntheses, spectroscopic and structural characterizations and metal ion binding properties of Schiff bases derived from 4′-aminobenzo-15-crown-5

A series of benzyloxybenzaldehyde derivatives (1-4) were synthesized by the reactions of 4-(bromomethyl)benzonitrile with 4-hydroxy-3-methoxybenzaldehyde (vanillin), 2-hydroxy-3-methoxybenzaldehyde (o-vanillin), 2-hydroxy-4-methoxybenzaldehyde and 2-hydroxy-5-methoxybenzaldehyde. Condensation reactions among the new benzyloxybenzaldehyde derivatives (1-4) with 4′-aminobenzo-15-crown-5 yielded the new Schiff base compounds (5-8). Sodium complexes (5a-8a) and potassium complexes (5b-8b) were prepared with NaClO₄ and KI, respectively. All of these synthesized compounds were characterized on the basis of FT-IR, ¹H and ¹³C NMR, mass spectrometry and elemental analyses data. The solid state structures of compounds 8 and 5a were determined by X-ray crystallography. The extraction abilities of compounds 5-8 were also evaluated in CH₂Cl₂ by using several main group and transition metal picrates, such as Na⁺, K⁺, Pb²⁺, Cr³⁺, Ni²⁺, Cu²⁺ and Zn²⁺.     

Synthesis of polyfunctionalized furans from 3-acetyl-1-aryl-2-pentene-1,4-diones

The BF₃-catalyzed cyclization of 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-e in the presence of water in boiling tetrahydrofuran gave bis(3-acetyl-5-aryl-2-furyl)methanes 2a-e in 26-79% yields along with a small amount of 3-acetyl-5-aryl-2-methylfurans 3a-e. The exact structure of 2a was determined by X-ray crystallography. The use of a half volume of the solvent for the reaction of 1a resulted in the formation of 2,4-bis(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-phenylfuran (4) together with 2a and 3a. A similar reaction of 1a was carried out in the presence of 3-acetyl-5-(4-methylphenyl)-2-methylfuran (3d) to afford 4-(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-(4-methylphenyl)-2-methylfuran (5) in 49% yield. The BF₃-catalyzed reaction of 1a with 2,4-pentanedione in dry tetrahydrofuran at 23°C gave 3-(3-acetyl-5-phenyl-2-furfuryl)-4-hydroxy-3-penten-2-one (6a) and 3-(3-acetyl-2-methyl-4-phenyl-5-furyl)-4-hydroxy-3-penten-2-one (7a) in 66 and 24% yields, respectively. The product distribution depended on the reaction temperature. A similar reaction of 1b-e also yielded the corresponding trisubstituted furans 6b-e and tetrasubstituted furans 7b-e in good yields. These results suggested the presence of the furfuryl carbocation intermediate A during the reaction. The one-pot synthesis of 6a and 7a was also achieved by a similar reaction using phenylglyoxal. The deoxygenation of 1a with triphenylphosphine gave 3a in 88% yield, while 1a was treated with concentrated hydrochloric acid to yield 3-acetyl-2-chloromethyl-5-phenylfuran (8) which was quantitatively transformed in ethanol into 3-acetyl-2-ethoxymethyl-5-phenylfuran (9) and in water into 3-acetyl-5-phenylfurfuryl alcohol (10), respectively. In addition, the Diels-Alder reaction of cyclopantadiene with 1a gave the corresponding [4+2] cycloaddition products 11 and 12.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.