Tumor inhibiting tetrapeptide bearing modified phenethyl amides

• US 5,635,483 A
• Filed: 12/03/1992
• Issued: 06/03/1997
• Est. Priority Date: 12/03/1992
• Status: Expired due to Term

• Current Assignee: Arizona Board of Regents (University of Arizona)
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Pettit, George R., Barkoczy, Jozsef
• Primary Examiner(s): Scheiner, Toni R.
• Assistant Examiner(s): HUFF, SHEELA JITENDRA
• Application Number:
  US07/985,827
• Time in Patent Office: 1,643 Days
• Field of Search: 514/17, 530/330
• US Class Current: 514/19.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof

Abstract

New tetrapeptides bearing modified phenethyl amides are elucidated and syesized and found to exhibit tumor inhibiting effects when measured against the NCI screen for six major types of human cancer and against the murine P388 lymphocytic cell line. The new modified tetrapeptides phenethyl amides are 6(a-k).

Claims

1. A compound having the following structural formula ##STR5## wherein R¹ is selected from the group consisting of OCH₃, NO₂, F, Cl, Br, and H;

R² is selected from the group consisting of OCH₃, H, and Cl; and

R³ is selected from the group consisting of H and Cl, provided that if R¹ is NO₂, Cl, F, or Br, R² =R³ =H;

that if R² =Cl then R¹ =R³ =H;

that if R³ =Cl then R² =R³ =H and that if R¹ =OCH₃, then R² =R¹ and R³ =H.

5. A compound according to claim 1 wherein R¹ =H or Cl, R² =H or Cl and R³ =Cl or H.

2. A compound having the following structural formula ##STR6## wherein R⁴ is selected from the group consisting of H and CH₃, R⁵ is selected from the group consisting of H and CH₃, R⁶ is selected from the group consisting of CH₃ and H, R⁷ is selected from the group consisting of H and OH, and R⁸ is selected from the group consisting of H and OH;

provided that either R⁷ or R⁸ =OH, that at least one of R⁴, R⁵ and R⁶ =CH₃ and that at least two of R⁴, R⁵, R⁶, R.sup.∂ and

R⁸ =H.

7. A compound according to claim 2 wherein R⁴ =H, R⁵ =CH₃, R⁶ =H, R⁷ =OH or H, R⁸ =OH or H and R⁷ ≠

R⁸.

3. A method of inhibiting the growth of cancer cells selected from the group of cell lines consisting of P388, OVCAR-3, SF295, A498, NCI-460, KM20L2 and SK-MEL-3, comprising of engaging said selected cell with a cell growth inhibitory amount of the compound having the following structural formula:

##STR7## wherein R¹ is selected from the group consisting of OCH₃, NO₂, F, Cl, Br, and H;

R² is selected from the group consisting of OCH₃, H, and Cl; and

R³ is selected from the group consisting of H and Cl, provided that if R¹ is NO₂, Cl, F, or Br, R² =R³ =H;

that if R² =Cl then R¹ =R³ =H;

that if R³ =Cl then R=R² =H and that if R¹ =OCH₃, then R² =R¹ and R³ =H.

6. A method according to claim 3 wherein R¹ =H or Cl, R² =H or Cl, and R³ =Cl or H.

4. A method of inhibiting the growth of cancer cells selected from the group of cell lines consisting of P388, OVCAR-3, SF295, A498, NCI-460, KM20L2 and SK-MEL-3, comprising of engaging said cell line with a cell growth inhibitory amount of the compound having the following structural formula:

##STR8## wherein R⁴ is selected from the group consisting of H and CH₃, R⁵ is selected from the group consisting of H and CH₃, R⁶ is selected from the group consisting of CH₃ and H, R⁷ is selected from the group consisting of H and OH, and R⁸ is selected from the group consisting of H and OH;

provided that either R⁷ of R⁸ =OH, that at least one of R⁴, R⁵ and R⁶ =CH₃ and that at least two of R⁴, R⁵, R⁶, R⁷ and R⁸ =H.

8. A method according to claim 4 wherein R⁴ =H, R⁵ =CH₃, R⁶ =H, R⁷ =OH or H, R⁸ =OH or H, and R⁷ ≠

R⁸.