The 2-amino group in classical folic acid analogues such as methotrexate (MTX, 1) and aminopterin (AMT, 2) is conventionally considered essential for biological activity, supported by historical studies and X-ray crystallography demonstrating its role in hydrogen bonding to the active site of dihydrofolate reductase (DHFR). However, Jones and co-workers showed that the 2-amino group in the potent thymidylate synthase (TS) inhibitor CB3717 could be replaced by hydrogen with only an 8-fold loss of TS inhibition and a 10-fold increase in potency against L1210 murine leukemia cells. This prompted us to synthesize the 2-desamino (3) and 2-desamino-2-methyl (4) analogues of AMT to determine (a) whether replacing the 2-amino group with hydrogen or methyl decreases DHFR inhibition and (b) whether these structural changes abolish tumor cell growth inhibition. We report the synthesis (adapted from Taylor's method using di-tert-butyl N-(4-aminobenzoyl)-L-glutamate as a key intermediate) and preliminary biological evaluation of 3 and 4. 3 and 4 showed DHFR IC₅₀ values of 19 μM and >50 μM, respectively—over 1000-fold lower than MTX's 0.02 μM. However, their growth inhibitory activity against L1210 cells (IC₅₀: 0.082 μM for 3, 0.042 μM for 4) and WI-L2 human leukemic lymphoblasts (IC₅₀: 0.081 μM for 3, 0.028 μM for 4) was only 6-9-fold lower than MTX. They retained good substrate activity for folylpolyglutamate synthetase (FPGS): 3 had a Kₘ of 26.4 ± 1.4 μM, 4 had a Kₘ of 31.7 ± 5.6 μM, comparable to AMT's Kₘ of 22.8 ± 6.4 μM. Reversal experiments with thymidine (10 μM) and hypoxanthine (100 μM) confirmed their antifolate mechanism—combined addition fully restored cell growth. These compounds represent a novel class of folate antagonists where the 2-amino group is replaced by nonpolar substituents; further studies on their mechanism of action and therapeutic potential are planned. For angiotensin II (AII) receptors, potent antagonists are traditionally obtained by modifying positions 1 (aspartic acid), 4 (tyrosine), and 8 (phenylalanine) of the AII sequence—e.g., saralasin ([Sar¹,Val⁶,Ala⁸]AII) with Sar¹ and aliphatic Phe⁸, and sarmesin ([Sar¹,(Me)Tyr⁴]AII) with Sar¹ and methylated Tyr⁴. Little is known about their chain-length requirements. Using the strategy that a peptide hormone's binding component alone can act as an antagonist (binding to the receptor without activating signaling), we hypothesized AII residues 1-7 define binding specificity while residue 8 mediates agonist/antagonist activity. We designed [Sar¹]angiotensin II-(1-7)-amide ([Sar¹]AII-(1-7)-NH₂, 1) by truncating the carboxy-terminus (removing residue 8) and introducing Sar¹ (a substitution known to increase potency in AII analogues). [Sar¹]AII-(1-7)-NH₂ was synthesized via solid-phase methods using an Applied Biosystems Model 430A peptide synthesizer and purified by preparative reverse-phase HPLC. In isolated rabbit aortic rings, [Sar¹]AII-(1-7)-NH₂ acted as a competitive AII antagonist: concentration-response curves showed rightward shifts in AII activity with increasing [Sar¹]AII-(1-7)-NH₂ concentrations, and a Schild plot yielded a slope of 1.08 ± 0.12 (consistent with competitive antagonism) and a pA₂ of 7.63 ± 0.20. This analogue provides entry to a new class of AII antagonists targeting the binding domain (residues 1-7) rather than modifying residue 8.