Synthesis of new bisaryl cyclopentathiophene and thieno-cyclopentoxazolidine derivatives as potential cytotoxic agents

Figures & data

Figure 1 Structure of cytotoxic cyclopentathiophene derivatives 1–3.

Scheme 1 Synthesis of compounds 3,8. Reagents: (i) AcONH₄, (CH₂)₂CO₂H, EtOH; (ii) TFA₂O, Et₂O; (iii) Br₂, CH₂Cl₂; (iv) SOCl₂; (v) AlCl₃, CH₂Cl₂; (vi) Br₂, AcOH; (vii) Na₂CO₃, Me₂CO; (viii) HCl gas, Me₂CO; (ix) ambient air; (x) (CCl₃O)₂CO, toluene.

Scheme 2 Synthesis of compounds 12–14. Reagents: (i) ArB(OH)₂, PdCl₂(dppf), TEA, DMF.

Scheme 3 Synthesis of compound 15. Reagents: (i) HCl 6N.

Scheme 4 Synthesis of compounds 16–17. Reagents: (i) ArB(OH)₂, PdCl₂(dppf), TEA, DMF.

Scheme 5 Synthesis of compounds 18–19. Reagents: (i) Br₂, CH₂Cl₂.

Table I.  Cytotoxicity of compounds 15–19 in the NCI's three-cell line one-dose primary anticancer assay, expressed as the percent growth at 10⁻⁴ M concentration.

Compd	Lung NCI-H460	Breast MCF7	CNS SF-268
15	19	60	33
16	46	53	70
17	80	74	113
18	112	63	127
19	114	76	128

Table II.  Cytotoxicity of compounds 1,3,15 in the NCI's in vitro human disease-oriented tumor cell line screening expressed as the log molar drug concentration required for 50% growth inhibition (log GI₅₀)

Compd	Leukemia RPMI 8226	Lung NCI- H522	Colon SW-620	CNS SF-539	Melanoma UACC-257	Ovarian ovcar-4	Renal CAKI-1	Prostate PC-3	Breast MDA-231	MGM^a
1	− 6.53	− 5.81	− 5.50	− 5.61	− 7.23	− 5.71	− 5.76	− 5.13	− 5.68	− 5.46
3	− 5.37	− 6.61	− 5.68	− 5.11	− 5.74	− 5.78	− 6.47	− 5.02	− 5.74	− 5.53
15	− 4.91	− 4.65	− 5.04	− 4.67	− 4.28	− 4.37	− 4.48	− 4.51	− 4.55	− 4.61

^a Mean Graph Midpoint for all human cancer cell lines tested.