Novel 6-5 Fused Ring Heterocycle Antifolates with Potent Antitumor Activity: Bridge Modifications and Heterocyclic Benzoyl Isosters of 2,4-Diamino-6,7-dihydro-5H-cyclopenta(d)pyrimidine Antifolate.

Abstract

Structural modifications of an extremely potent inhibitor of dihydrofolate reductase (DHFR) activity and tumor cell growth, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1), have led to the synthesis of new cyclopenta[d]pyrimidine-based antifolates, including those with low alkyl substituted trimethylene bridges (2a, b) and isosterically modified bridges (ethyleneoxa, 2c; ethyleneamino, 2d; the N-methyl- and N-ethyl derivatives of 2d, 2e, f) and those in which the benzene ring of 1 has been replaced by heterocyclic isosters (indole, 2g; indoline, 2h; thiophene, 2i). These new analogs are highly potent as DHFR and cell growth inhibitors, and most of them are more potent than methotrexate (MTX) and 10-ethyl-10-deazapterin (10-EDAM) in inhibiting tumor cell growth (P388 MTX-sensitive and MTX-resistant, colon 26 and KB) on 72 h drug exposure. Among them, 2a (the 10-methyl derivative of 1) and 2i were most potent, being 2- to 3-fold more potent than 10-EDAM. On 4 h drug exposure, the growth-inhibitory activity of these analogs was radically influenced by even minor structural changes. Compounds 1, 2a--e, g--i were much more cytotoxic in colon 26 cell line than were MTX and 10-EDAM, with 2d and 2i being most potent, followed by 2a. Structure-activity relationships and their possible significance are discussed.

Photoinitiators with functional groups. VII. Covalently bonded camphorquinone—amines

“…For type B structures, modified amines 14 21 and 16, 22 with varying spacer lengths, were prepared from esterified 4‐(methylamino)‐benzoic acid 13 20 by N ‐alkylation (Scheme ). Suitable reference CIs 15 30 and 17 were prepared by the reaction of 14 or 16 with ethylbromide.…”

Tryptophan and thiosemicarbazide derivatives: design, synthesis, and biological evaluation as potential β-d-galactosidase and β-d-glucosidase inhibitors

“…After stirring for 15 min, a solution of L-tryptophan methyl ester hydrochloride 2 (1.37 g, 5.4 mmol) and triethyl amine (1 mL) in dry DMF (4 mL) was added. The solution was stirred overnight under N 2 gas, most of DMF was evaporated under reduced pressure, and the residue was treated with water and kept in the freezer for 1 h. The solution was then filtrated off to afford 3a-d in a good yield (Kotake et al, 1995). The prepared compounds were recrystallized from ethanol.…”

“…The titled derivatives were synthesized by similar procedure described by Kotake et al (1995). Compounds 3a-d (5.5 mmol) were dissolved in 5 % NaOH (40 mL) and stirred overnight; the solution was acidified with diluted HCl, and the precipitate that formed was collected by General procedure for synthesis of (S)-ethyl N,N 0 -bis(arylcarbonyl)lysinoate (6a-c)…”

Structure–Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree–Fock Calculations

“…3,13 The synthesis of target structure 7-N-phenyl 8 commenced with the synthesis of secondary amine 14 by N-alkylation of commercially available aniline and ethyl 2-bromoacetate in 46% yield (Scheme 1). 17 Subsequently, N-alkylation of 14 with chloroacetone, NaI, and K 2 CO 3 in THF afforded tertiary amine 15 in 31% yield.…”

“…This afforded the title compound as a pale-yellow oil (448 mg, 1.73 mmol, 31% yield); R f 0.25 (EtOAc/heptane 1:2). 1 Ethyl 2-(Benzylamino)acetate (17). A solution of ethyl bromoacetate (924 μL, 8 mmol) in dry THF (4 mL) was added dropwise over 10 min to a cooled solution of benzylamine (2 mL, 18 mmol) in dry THF (20 mL) at 0°C under a N 2 atmosphere.…”